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At least 1,207 records · Page 67Linked to original sources
PubMed2001

Altretamine is an effective palliative therapy of patients with recurrent epithelial ovarian cancer.

BACKGROUND: Management of patients with recurrent epithelial ovarian cancer is difficult. Although several agents are active, responses are short-lived and observed in only a small number of patients. Side effects of these drugs are substantial. There is a need for more effective and less toxic therapies. Altretamine is a well tolerated oral agent with minimal toxicity. There are only a few trials evaluating its efficacy as a single agent in recurrent epithelial ovarian cancer. METHODS: We prospectively studied patients with recurrent epithelial ovarian cancer who were able to take oral medication and had adequate bone marrow, liver and renal functions. All had been previously treated with at least one platinum-based chemotherapy regimen and had either relapsed or failed to achieve an adequate response. RESULTS: Seventeen patients were studied. The commonest histological subtype was serous adenocarcinoma. Seven patients had platinum refractory disease. The mean duration of therapy was 6.1 months. Six patients (35%) achieved complete or partial remission, time to progression was 6.0 months and mean overall survival was 15.1 months. Toxicity was primarily nausea, vomiting and asthenia and was easily manageable. CONCLUSION: Altretamine is an acceptable and apparently less toxic alternative to other cytotoxic drugs used for palliation of patients with recurrent epithelial ovarian cancer.

Administration, Oral↗
PubMed2002

Low-dose weekly paclitaxel as second-line treatment for advanced non-small cell lung cancer: a phase II study.

PURPOSE: To assess the activity and toxicity of low-dose weekly paclitaxel in patients with non-resectable or metastatic non-small cell lung cancer (NSCLC) and who had disease recurrence or failure with previous chemotherapy. PATIENTS AND METHODS: Forty patients with NSCLC previously treated with platinum-based chemotherapy received weekly paclitaxel 80 mg/m(2) as a 1 h infusion. The median age was 63 years (range 42-77 years); 25 patients had Eastern Cooperative Oncology Group performance status (PS) 1 and 15 had PS 2. Thirty-one patients had stage IV disease and nine stage III (eight stage IIIB and one stage IIIA). RESULTS: A total of 364 weeks of treatment were administered (median 8 weeks, range 2-17 weeks). There were no episodes of grade 3 or 4 haematological toxicities. Severe non-haematological toxicity was uncommon: grade 1-2 asthenia in 50%; grade 1-2 motor neuropathy in 45% and grade 3 in 10%; grade 1-2 sensory neuropathy in 62% of patients. Alopecia was mild. The overall response rate was 37.5% (95% CI, 23.9-55): 2 CR, 13 PR, 15 SD, 8 PD, 2 NE. Median overall survival was 9.7 months (95% CI, 6.5-12.8). Median time to progression was 5.4 months (95% CI, 1.8-8.9). CONCLUSION: A low-dose weekly paclitaxel regimen had good clinical efficacy with low toxicity in this group of patients with poor prognosis. This regimen increases the therapeutic options available for second-line therapy in NSCLC patients.

Adult↗
PubMed2006

A phase II trial of docetaxel plus capecitabine in patients with previously treated non-small cell lung cancer.

BACKGROUND: A combination of docetaxel (T) and capecitabine (X) showed synergistic effects in preclinical studies and phase III randomized trials of metastatic breast cancer. We conducted this phase II study to examine its efficacy in previously treated non-small cell lung cancer (NSCLC) patients. METHODS: Patient eligibility required advanced NSCLC with measurable lesion(s), at least one prior regimen failure and Eastern Cooperative Oncology Group (ECOG) performance status 0-2. Treatment consisted of T 36 mg/m(2) i.v. on days 1 and 8 plus X 1000 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level I) or T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle (level II). RESULTS: A total of 35 patients (M/F=24/11) were enrolled; 29 had received one prior regimen and 19 had received platinum-based regimens. Significant non-hematologic toxicities were observed after the treatment given at level I, including one treatment-related death. Subsequently 29 patients were treated at level II. The treatment at level II was well tolerated with grade 3 or 4 neutropenia only in 10%, grade 3 asthenia in 21% and stomatitis in 14% of patients. Four (15%) of 27 evaluable patients had partial response (PR) at level II and eight (30%) had stable disease (SD). CONCLUSIONS: The TX regimen showed modest antitumor effects in patients with previously treated NSCLC. For further studies, we recommend T 30 mg/m(2) i.v. on days 1 and 8 plus X 625 mg/m(2) p.o. b.i.d. on days 1-14 of a 21-day cycle.

Adenocarcinoma↗
PubMed2005

Dose-dense adjuvant chemotherapy in early breast cancer patients: results from a randomized trial.

BACKGROUND: To determine whether a dose-dense regimen improves outcome in early breast cancer patients, we compared outcomes with the same fluorouracil, epirubicin, and cyclophosphamide (FEC) chemotherapeutic regimen administered every 3 weeks (FEC21) or administered every 2 weeks (FEC14 including support with filgrastim, a granulocyte colony-stimulating factor) in a multicenter phase III randomized trial. METHODS: A total of 1214 patients with early-stage breast cancer were randomly assigned to receive six cycles of FEC14 (604 patients) or of FEC21 (610 patients). Study endpoints were overall survival and event-free survival. Associations were assessed by multivariable analysis with adjustment for age; tumor size; grade; proliferative rate; and menopausal, lymph node, estrogen receptor, and progesterone receptor status. All statistical tests were two-sided. RESULTS: Patients in the FEC14 arm had fewer dose reductions or treatment delays or discontinuation (26%) than those in the FEC21 arm (33%) (difference = 7%, 95% confidence interval [CI] = 2% to 12%; P = .008). FEC14 therapy, compared with FEC21 therapy, was associated with more asthenia (36% versus 29%, difference = 7%, 95% CI = 2% to 12%; P = .01), bone pain (33% versus 4%, difference = 29%, 95% CI = 25% to 33%; P < .001), anemia (38% versus 19%, difference = 19%, 95% CI = 14% to 24%; P < .001), and thrombocytopenia (8% versus 2%, difference = 6%, 95% CI = 4% to 9%; P < .001), but with less leukopenia (12% versus 45%, difference = 33%, 95% CI = 28% to 37%; P < .001). No acute myelogenous leukemia or myelodysplastic syndrome was observed. At a median follow-up of 10.4 years, no statistically significant difference in the hazard of death (hazard ratio [HR] = 0.87, 95% CI = 0.67 to 1.13) or recurrence (HR = 0.88, 95% CI = 0.71 to 1.08) was found between FEC14 and FEC21 groups after adjustment by multivariable analysis. Although the study was underpowered for subset analysis, we found no evidence that the effect of the treatment type was associated with any of the potential prognostic factors. CONCLUSION: Our results support the long-term safety of FEC14 chemotherapy as an adjuvant treatment of breast cancer. However, this therapy was not associated with improved outcome, but because of the limited statistical power of our study, we cannot rule out a modest improvement in outcome associated with FEC14 therapy.

Adult↗
PubMed2001

The tolerance and efficacy of interferon-alpha in haemodialysis patients with HCV infection: a multicentre, prospective study.

BACKGROUND: A prospective multicentre study was initiated in HCV-infected haemodialysis patients to assess the tolerance and efficacy of alpha-2b interferon. METHODS: We had planned to include 120 patients with HCV RNA detectable by polymerase chain reaction (PCR) (Amplicor Roche) and histologically documented chronic hepatitis. The dose of alpha-interferon was 3 million units (MU) three times weekly (TTW), to be reduced to 1.5 MU TTW in case of side-effects. Tolerance was evaluated monthly; virological efficacy was evaluated by PCR. A liver biopsy was performed at month 18 (M18). RESULTS: (a) TOLERANCE: After 37 patients had been included, the study was discontinued by the promoting institution because of severe side-effects requiring that treatment be stopped in 19 patients. The side-effects were: cardiac (4) neuropsychiatric (2), digestive (3), acute necrosis of the graft (1), severe asthenia (9), minor side-effects were observed in 22 patients. A complete 12-month course was completed in 12 patients for the 3 MU TTW dose and in six patients for the 1.5 MU TTW reduced dose. Normal ALT level (OR, 0.16; CI 95%, 0.03-0.89) at inclusion was associated with interruption of treatment (univariate analysis). (b) EFFICACY: Sustained virological response was observed in only seven (18.9%), of the 18 patients who completed the treatment (38%). Increased ALT at inclusion (OR, 1.04; CI 95%, 1.01-1.09) and cumulated doses of interferon (OR, 1.01; CI 95%, 1.004-1.026) were jointly associated with a sustained response, while positive PCR at M2 was strongly predictive of treatment failure. CONCLUSION: Tolerance of interferon is poor in haemodialysis patients. Sustained response is fairly high in patients who have 12 months of treatment and seems to be based on the immune status of the patients (ALT) and the cumulative doses of interferon.

Adult↗
PubMed2003

Efficacy and safety of lowering immunosuppression to treat CMV infection in renal transplant recipients on valaciclovir prophylaxis: a pilot study.

BACKGROUND: Routine cytomegalovirus (CMV)-pp65 antigenaemia monitoring shows that some patients will develop pp65 antigenaemia during valaciclovir prophylaxis or after cessation of treatment. The aim of this pilot study was to evaluate the safety and efficacy of lowering immunosuppression in kidney transplant recipients who exhibit mildly symptomatic CMV infections while on valaciclovir prophylaxis. METHODS: We selected 12 patients who experienced mildly symptomatic CMV infections defined as a positive CMV-pp65 antigenaemia test associated with either neutropenia, asthenia or arthralgia, but no fever. All of them received prophylaxis with valaciclovir for at least 3 months. Testing for CMV-pp65 antigenaemia was performed weekly for 6 months. RESULTS: The mildly symptomatic infections occurred at a median interval of 69 days after transplantation-during prophylaxis in eight cases and after valaciclovir discontinuation in the other four cases. All of them were effectively managed by lowering immunosuppressive therapy, leading to the disappearance of symptoms and CMV antigenaemia reduction. No immunological complication or recurrence of CMV infection or disease was noted. I.v. ganciclovir never became necessary. CONCLUSION: The mildly symptomatic CMV infections occurring in valaciclovir-treated patients may be managed efficiently and without immunologic complication by lowering immunosuppressive therapy.

Acyclovir↗
PubMed1996

Subcutaneous recombinant interleukin-2 (rIL-2) in out-patients with metastatic renal cell carcinoma. Results of a multicenter SCAPP1 trial.

BACKGROUND: This multicenter phase II trial was conducted in order to evaluate the efficacy and toxicity of the subcutaneous route of administration of rIL-2 in the treatment of patients with metastatic renal cell carcinoma and to check whether an increased cumulative dose of rIL-2 increases efficacy. PATIENTS AND METHODS: Thirty-nine patients with metastatic renal cell carcinoma were included in this study. During the induction period, rIL-2 was administered subcutaneously 5 days a week for 8 weeks. The weekly dosages were 90 MIU during weeks 1 and 6;63 MIU during weeks 2 to 4 and 7 to 9. After evaluation, responders and patients with stable disease received maintenance treatment which was discontinued upon the appearance of disease progression or unacceptable toxicity. During the maintenance period, rIL-2 was administered 5 days a week for 4 weeks followed by a 2-week rest period. The weekly dosages were 90 MIU in week 1 and 63 MIU in weeks 2 to 4. RESULTS: After completion of induction treatment, 7 of 39 evaluable patients (18%) had objective responses (95% CI: 9% to 37%) with one complete response. Treatment was interrupted or reduced due to toxicity for seven patients: Neuropsychiatric symptoms (3 patients), joint pain (1 patient), major asthenia and anorexia (1 patient), stroke (1 patient), and septicemia (1 patient). Other systemic side effects in the remaining patients were acceptable. Seventeen patients received maintenance treatment. In none of the patients did the response status improve during this maintenance period. The median follow-up of all of the patients included was 19 months. The one- and two-year survivals were 65% and 33%, respectively, ad the median duration of response was 11 months (5 to 16+). CONCLUSIONS: This multicentric study confirms the efficacy of subcutaneously-administered rIL-2 in patients with metastatic renal cell carcinoma in terms of both response rate and survival. The role of a maintenance therapy needs further evaluation.

Adult↗
PubMed1996

A randomized phase II study with two schedules of the novel indoloquinone EO9 in non-small-cell lung cancer: a study of the EORTC Early Clinical Studies Group (ECSG).

In a multicentre randomized trial of the EORTC-ECSG, we have treated 38 chemotherapy naïve patients with advanced non-small-cell lung cancer (NSCLC) with EO9, a novel bio-reductive alkylating indoloquinone. The drug was given at two different dose schedules by a single bolus i.v. injection: arm A 12 mg/m2 weekly and arm B 22 mg/m2 every three weeks. All together 185 courses were administered (145 in arm A and 40 in arm B). The major toxicity was reversible proteinuria more frequently occurring in the three-weekly schedule (arm A 34.5% vs. arm B 62.5%). Creatinine elevation, fluid retention and pericardial or pleural effusion were also recorded in a limited number of patients. Other common toxicities more frequent in the three-weekly administration were asthenia (21% vs. 35% of cycles), nausea (15% vs. 27.5% of cycles) and vomiting (5% vs. 17.5% of cycles). Toxicities were mainly of grade I and II. No responses have been observed. Five patients (26%) on arm A and eight (53%) on arm B experienced stable disease. These doses and schedules of EO9 do not yield activity in NSCLC.

Adult↗
PubMed1995

Phase II trial of CPT-11 in patients with advanced pancreatic cancer, an EORTC early clinical trials group study.

BACKGROUND: CPT-11 (irinotecan) is a semi-synthetic derivative of camptothecin and exerts its activity by inhibiting DNA topoisomerase I. A phase II study of this drug was performed in patients with pancreatic cancer. PATIENTS AND METHODS: Eligibility criteria included advanced non-chemotherapy-pretreated pancreatic cancer. CPT-11 was administered as a 30-minute i.v. infusion at a dose of 350 mg/m2 diluted in 250 ml normal saline every 3 weeks. RESULTS: Thirty-four eligible patients were enrolled in the study, thirty-two of them were evaluated, and three achieved partial responses (9%; 95% C.I. = 3%-25%). The duration of response was 7.2, 7.5 and 7.8 months, respectively. Thirteen patients had no change, fourteen patients had progressive disease and two had early progressive disease. The median duration of survival for all patients treated was 5.2 months. The main toxicities (CTC grade > or = 3) were diarrhea, leukocytopenia, asthenia, nausea and vomiting in, respectively, 7%, 16%, 8%, 6%, 4% of the courses. These toxicities were reversible and manageable with anti-emetics and prophylactic or curative antidiarrheal agents. CONCLUSION: CPT-11 is an interesting moderately effective drug in pancreatic cancer.

Adult↗
PubMed1994

Complete sinus arrest during diltiazem therapy; clinical correlates and efficacy of intravenous calcium.

The occurrence of severe sinus node dysfunction in 10 patients (three males and seven females; mean age 78.5 +/- 3.4, range 57-92 years) receiving oral diltiazem therapy (mean 190 +/- 20 mg/24 h, range 90-300) is described. Six of them were concomitantly taking amiodarone and/or beta-blocking agents. On admission, seven patients exhibited systemic hypotension and nine complained of asthenia and/or dizziness or drowsiness. ECG findings showed in all a persistent sinus arrest with atrial, junctional or ventricular escape, leading to a mean heart rate of 40.2 +/- 3 beats.min-1 (range 25-56). All patients had chronic renal failure on biological tests, with a mean endogenous creatinine clearance of 25 +/- 3 ml.min-1 (range 12-36). Intravenous calcium hydrochloride (mean 1.4 +/- 0.2 g, range 1-2), given in nine patients, rapidly restored stable sinus activity in seven. We suggest that diltiazem should be given cautiously to ageing patients with chronic renal failure, and confirm the efficacy of intravenous calcium in reversing calcium channel blocker toxicity on sinus node.

Aged↗
PubMed2003

Fibromyalgia and the therapeutic domain. A philosophical study on the origins of fibromyalgia in a specific social setting.

OBJECTIVES: Fibromyalgia has always attracted controversy. Wolfe states that fibromyalgia will always exist regardless of the name given to the syndrome. Hadler describes fibromyalgia as a form of illness behaviour escalated by labelling. However, we believe that fibromyalgia, as other functional somatic syndromes, is not waiting below the surface until it becomes manifest by labelling. METHODS: We developed our hypothesis on the relationship between a specific social setting (called the therapeutic domain) and fibromyalgia using empirical philosophical arguments based on Foucault and Hacking. A therapeutic domain is a real and heterogeneous medical domain in which people, their thoughts and practices, and medical technology in any form coexist and communicate. In this domain blood is aspirated, radiographs are taken and classification criteria are made and applied. It is a domain where patient and therapist have initiated a relationship, which is influenced by the media and political pressure. This results in a looping effect where classification criteria and images give structure to perceptions and form the description for human behaviour; the person thus diagnosed (!) constantly has to grow into the conformity of these classification criteria, which also have to be constantly revised. The fibromyalgia concept becomes manifest in an individual as non-specific aches and pains along with other features. RESULTS: In other times and settings this resulted in analogue syndromes like railway spine, telegraph wrists, neurocirculatory asthenia or perhaps repetitive strain injury. In the application of American College of Rheumatology fibromyalgia classification criteria, labels and medical technology it is possible that invisible experiences manifest themselves in a therapeutic domain. It is not only a phenotype induced by the physician, but in this domain a certain power creates reality making the 'disease' become manifest. CONCLUSION: The only certainty in fibromyalgia is that it is still being diagnosed. For prevention and treatment of fibromyalgia, doctors as well as politicians and media have to start by fundamentally changing the therapeutic domain. In such a renewed setting, fibromyalgia cannot become manifest in an individual and thus fibromyalgia syndrome can no longer exist. A firm public message that symptoms can be psychological in origin to prevent their spread, as Wessely recently stated in the comparable case of mass psychogenic illness, is only a part of the answer.

Fibromyalgia↗
PubMed1989

Combination chemotherapy with cytosine arabinoside (Ara-C) and cis-diamminedichloroplatinum (CDDP) for squamous cancers of the upper aerodigestive tract.

Based on the demonstration of in vitro and in vivo synergy between cytosine arabinoside (Ara-C) and cis-diamminedichloroplatinum (CDDP), we designed a Phase II trial of Ara-C plus CDDP for patients with advanced squamous cancers of the head and neck and esophagus. Sixteen patients were treated on a unique schedule of continuous-infusion Ara-C, 30 mg/m2/day over 72 h, plus CDDP, 30 mg/m2/day at hours 12, 36, and 60 of the Ara-C infusion. The objective response rate was 38% (95% confidence limits 14-62%), with two patients achieving complete clinical and radiographic response (9 and 27+ months duration) and four partial responses (median duration 4 months, range 1-7 months). There was no CDDP-related nephro- or neurotoxicities, but a flu-like syndrome of anorexia and asthenia was common. Myelosuppression was the dose-limiting toxicity, necessitating Ara-C dose adjustments in 11 cycles of therapy and leading to fatal sepsis in one patient. We conclude that the activity of this combination, though comparable to that of other CDDP-containing regimens, offers no significant therapeutic advantage, and given the excessive hematologic toxicity, should not be investigated further.

Aged↗
PubMed1996

Phase I-II trial of recombinant interferon alpha-2b with cisplatin and 5-fluorouracil in recurrent and/or metastatic carcinoma of head and neck.

The aims of this study were to establish the feasibility and toxicity of the biochemical modulation of the cisplatin (CDDP)-5FU combination by interferon alpha-2b (INF), and to assess its therapeutic efficacy in recurrent and/or metastatic squamous cell carcinoma of the head and neck (SCCHN). The mandatory eligibility criteria included histologically proven SCCHN; a performance status <2; adequate bone marrow, hepatic, renal, and cardiac functions; and measurable and/or evaluable disease. The protocol was CDDP, 100 mg/m2 i.v. day 1; 5-FU, 1,000 mg/m2 in a c.i.v. infusion over 96 h; and INF 3.10(6) U/day s.c., begun 2 h before cisplatinum for 5 consecutive days, repeated every 3 weeks. Twenty patients were included and received 76 cycles (median number cycles/patient = three). Eighteen patients were evaluable for activity with an overall response rate (RR) of 30% [2 complete responses (CR) + 4 partial responses (PR)], which was 55% (5/9) in previously untreated and 9% (1/11) in previously treated patients. Myelosuppression (50%), mucositis (40%), loss of electrolytes (15%), and asthenia (20%) were the most frequent severe toxic effects. Notwithstanding, the protocol was feasible and well tolerated in this overall population with a poor prognosis. Median duration of response was 8 months, and median survival for the overall population was 8.5 months. This schedule is the test arm of an ongoing international multicentric phase III trial versus standard CDDP-5FU in the same SCCHN population.

Adult↗
PubMed2001

Sequential chemoradiotherapy with docetaxel, cisplatin, and 5-fluorouracil in patients with locally advanced head and neck cancer.

The purpose of this phase II trial was to evaluate the toxicity of a sequential chemoradiotherapy approach using docetaxel, cisplatin, and 5-fluorouracil (5-FU) (DCF) with granulocyte colony-stimulating factor support in previously untreated patients with locally advanced head and neck cancer (HNC). Secondary endpoints included preliminary assessment of response. Patients with locally advanced HNC, a World Health Organization performance status 0 to 2, and no prior history of chemotherapy or radiotherapy were included. Treatment consisted of docetaxel 80 mg/m2 (1-hour infusion) on day 1, cisplatin 40 mg/m2 (1-hour infusion) on days 2 and 3, and 5-fluorouracil 1,000 mg/m2 (24-hour continuous infusion), on days 1 to 3, repeated every 28 days for a maximum of 4 cycles per patient. All patients received granulocyte colony stimulating factors subcutaneously between days 4 and 9. Radiation therapy (RT) to the primary tumor site and neck lymph nodes was planned within 5 weeks of the last cycle of chemotherapy. The primary tumor site received 60 to 70 Gy. Twenty patients (median age 56 years, range: 40-72 years) received a total of 60 cycles of DCF. The median number of cycles was 3 (range: 1-4 cycles). All patients were evaluable for toxicity and response. The most common acute nonhematologic toxicities from DCF induction chemotherapy included alopecia, mucositis, peripheral sensory neuropathy, onycholysis, and asthenia. Febrile neutropenia developed in two patients and grade IV diarrhea in one patient. There were no treatment-related deaths. The overall response rate (RR) after DCF induction chemotherapy was 90% (95% confidence interval [CI]: 76.8-103.1%). After the completion of RT, the overall RR was 95% with a complete response rate of 73% (95% CI: 49.9-90.1%). Organ preservation was achieved in eight patients with laryngeal cancer and one patient with base of tongue involvement. After a median follow-up of 36 months (range: 5-43 months) the median disease-free and overall survival have not been reached yet. The 1- and 2-year survival rates were 85% and 60%, respectively. Sequential chemoradiotherapy with DCF and growth factor support is feasible and very active, with durable responses in patients with locally advanced head and neck cancer. Further evaluation of this modality is justified in the context of a clinical trial.

Adult↗
PubMed2003

Phase II trial of the use of gemcitabine and 5-fluorouracil in the treatment of advanced pancreatic and biliary tract cancer.

In this phase II trial, we used the combination of gemcitabine and 5-fluorouracil (5-FU) to treat 26 patients: 17 (65%) with advanced pancreatic adenocarcinoma and 9 (35%) with advanced biliary tract adenocarcinoma (10 locally advanced and 16 metastatic); 15 (57.7%) male and 11 (42.3%) female; median age 58 (range, 39-68); median performance status 2 (range, 1-3). A total of 102 cycles were administered (median, 4 per patient). There were 8 objective responses, plus 1 complete response not confirmed by second-look laparotomy, thus the overall objective response rate was 30.7% (95% CI 12%-47%). Among the patients with biliary tract carcinoma, 33% (3/9) had PR. Six (23%) patients had stable disease (SD). All 8 responders and 3 of the patients with SD experienced clinical benefit (42%). The median overall survival was 9 months (range, 6-38), and the 1-year survival rate was 30%. The regimen was very well tolerated. One patient developed reversible World Health Organization grade IV febrile neutropenia. We observed grade III neutropenia in 11 (11%) cycles; grade III thrombocytopenia in 7 (7%) cycles; grade III mucositis in 7 (7%) cycles; and grade III diarrhea in 10 (10%) cycles. Asthenia grades I and II occurred in 30% of cycles and flulike syndrome grade II in 11 (11%) cycles. The combination of gemcitabine and 5-FU in patients with advanced pancreatic or biliary tract cancer produces promising activity and tolerability with the added potential for clinical benefit, and thus warrants further investigation.

Adenocarcinoma↗
PubMed1997

'Tomudex' (raltitrexed) development: preclinical, phase I and II studies.

Raltitrexed ('Tomudex', formerly ZD1694) is a new active drug for advanced colorectal cancer, an area that has been without new drugs for over 40 years. It has a convenient dosing schedule and a potential for lower toxicity which represent important advantages over existing treatments. Advanced colorectal cancer is currently treated with 5-fluorouracil, generally in combination with other agents such as leucovorin. This leads to complex dosing schedules with increased activity but potentially serious toxicity. Raltitrexed is a novel cytotoxic agent, rationally designed to inhibit a specific molecular target, thymidylate synthase. In contrast to other current agents, raltitrexed inhibits thymidylate synthase directly, specifically and non-competitively, which may lead to an improved toxicity profile. It is retained within cells as polyglutamate metabolites, allowing a more convenient dosing schedule than for 5-fluorouracil. Phase I and pharmacokinetic studies established the optimum dosing schedule as 3 mg/m2, administered in a single 15-min intravenous infusion once every 3 weeks. In a phase II study in 177 patients with advanced colorectal cancer, this dose produced a response rate of 26% and median survival of 11.2 months. The safety profile was acceptable, the main adverse events being myelosuppression, gastrointestinal toxicity, asthenia and transient asymptomatic increases in liver transaminases without evidence of any other liver dysfunction. Activity of raltitrexed has also been observed in a range of other solid tumours, including breast, pancreatic, non-small-cell lung and refractory ovarian cancer.

Antimetabolites, Antineoplastic↗
PubMed1997

Overview of the tolerability of 'Tomudex' (raltitrexed): collective clinical experience in advanced colorectal cancer.

The tolerability of raltitrexed ('Tomudex', formerly ZD1694) was examined during phase I, II and III clinical studies involving around 1000 patients with advanced colorectal cancer. The dose-limiting toxicities in the phase I studies were gastrointestinal toxicity, haematological suppression and asthenia. Adverse events during phase II and III studies were consistent with those seen during phase I. In all comparative studies, mucositis and leucopenia were markedly less frequent and less severe in patients treated with raltitrexed than with 5-fluorouracil + leucovorin.Thrombocytopenia was more common with raltitrexed but was not associated with an increase in clinically significant haemorrhage. Elevated transaminases were frequently reported with raltitrexed but were usually reversible with continued dosing and were not associated with clinical sequelae. Patients treated with 5-fluorouracil + leucovorin experienced greater toxicity during early treatment cycles than those treated with raltitrexed. Fewer dosage reductions due to toxicity and greater quality-of-life benefits were observed in these early treatment cycles in patients treated with raltitrexed. Moreover, the incidence of fatal adverse events in patients given the recommended dose of raltitrexed was similar between groups. Raltitrexed thus provides some tolerability advantages compared with 5-fluorouracil + leucovorin, mainly with respect to leucopenia and mucositis, and less overall toxicity in early treatment cycles. The toxicity profile of raltitrexed is that expected of an antimetabolite.

Antimetabolites, Antineoplastic↗
PubMed1999

An economic evaluation of Tomudex (raltitrexed) and 5-fluorouracil plus leucovorin in advanced colorectal cancer.

Our objective was to establish the balance between costs and effects of treatment with Tomudex (raltitrexed) as an alternative to treatment with 5-fluorouracil (5-FU) plus leucovorin (LV) in patients with advanced colorectal cancer. Data were used from an international, open label randomized clinical trial. Costs were calculated by multiplying resource utilization data with Dutch estimates of unit costs. Effects have been expressed in terms of 6 months and 1 year survival, and in terms of the number of patients without severe adverse events including WHO grade 3 and 4 leucopenia, mucositis, anemia and severe asthenia. Cost effectiveness is expressed in terms of costs per additional day of survival and costs per additional patient without any severe adverse event. The clinical results did not show significant survival differences implying great uncertainty about the cost-effectiveness of raltitrexed in terms of additional costs per additional life-year gained. However, 80% of the initially higher cost of raltitrexed ($3132 per patient) is compensated by savings due to a more convenient administration scheme leading to a net cost of $626 per patient treated. Weighed against the decrease in adverse events, a cost-effectiveness ratio results of $3936 per additional patient free of any severe adverse event. More favorable estimates result when the convenience of the administration scheme is valued in positive monetary terms.

Antineoplastic Agents↗