M. González Barón

Efficacy, tolerability and management of raltitrexed (Tomudex) monotherapy in patients with advanced colorectal cancer. a review of phase II/III trials.

Raltitrexed (Tomudex), a thymidylate synthase inhibitor, is an alternative to 5-fluorouracil (5-FU)/leucovorin (LV) for the first-line treatment of advanced colorectal cancer. Following the completion of four phase III studies with raltitrexed at the recommended dose of 3.0 mg/m(2), it is opportune to review the efficacy and tolerability data of raltitrexed and suggest guidelines for appropriate patient management. Data are analysed from four phase III and five phase II studies including over 1300 patients with advanced colorectal cancer, some of whom were elderly or received higher doses of raltitrexed. Median survival with raltitrexed was comparable to that of bolus or infusional 5-FU/LV in three of the four randomised studies and objective response rates in the four trials were similar for the two agents. Response rates were at least comparable in elderly patients in phase II studies. For the majority of patients, treatment with raltitrexed was well tolerated even at doses higher than that recommended or in the elderly. As with other cytotoxic agents, serious and potentially life-threatening side-effects can occur; nevertheless, adherence to simple patient guidelines should minimise the incidence of serious side-effects with raltitrexed; these include the assessment of renal function before each and every treatment, dosage adjustment in the presence of renal impairment and close monitoring with prompt treatment of toxicities, particularly diarrhoea and neutropenia.

Breast Cancer Prognosis Determined by Gene Expression Profiling: A Quantitative Reverse Transcriptase Polymerase Chain Reaction Study

PURPOSE We sought to reproduce with quantitative reverse-transcriptase polymerase chain reaction (qRT-PCR) the results obtained with a 70-gene expression profile that has been described previously in breast cancer. PATIENTS AND METHODS Frozen breast cancer samples from patients who were operated on were used to isolate tumor RNA. Ninety-six patients with stage I to II disease were included. Median age was 57 years (range, 27 to 80 years). Forty-eight patients had lymph node-negative and 48 lymph node-positive disease. qRT-PCR amplifications were performed and the results were correlated with clinical data. RESULTS After a minimum follow-up of 5 years, 25 patients had a relapse. The gene profile divided patients into two groups with poor and good prognosis. Significant differences with regard to grade of differentiation, size and hormone receptors were seen between the two groups. The gene profile was significantly associated with relapse-free survival and overall survival in the whole group of 96 patients. Multivariate analysis showed that only lymph node status and gene profile were significantly correlated to overall survival. CONCLUSION qRT-PCR reproduced the results obtained with microarrays for a prognostic gene profile in women with early-stage breast cancer.

Uracil and tegafur modulated with leucovorin

In spite of the high prevalence of cancer in the elderly, little information is available about the efficacy and toxicity of chemotherapy in elderly patients. In a previous study, the authors demonstrated that the combination of uracil and tegafur (UFT) with leucovorin (LV) was active and well tolerated in patients with advanced colorectal carcinoma (ACC). The objective of the current study was to determine the efficacy and toxicity of this regimen in elderly patients with ACC.

Employment in a cohort of breast cancer patients

BACKGROUND Breast cancer survivors can have problems in returning to work. However, the importance of work to cancer survivors has until recently received little attention. AIMS To investigate employment- and work-related disability in a cohort of breast cancer patients to identify possible discrimination and other obstacles to remaining in work. METHODS Questionnaire study of breast cancer patients employed at diagnosis and where diagnosis had been confirmed at least 6 months before the interview. Participants completed a questionnaire concerning cancer-related symptoms and work-related factors and clinical details were obtained from their medical records. RESULTS The study included 96 consecutive patients with breast cancer aged between 18 and 65 years. In total, 80% of patients were unable to work after diagnosis, but 56% returned to work at the end of treatment. The sequelae of the disease or its treatment and the stage of disease were independently associated with the ability to work after the end of treatment. Only one patient did not tell his/her employers and coworkers about his/her disease. In total, 29% noticed changes in their relation with co-workers and managers, usually in the sense that they tried to be helpful. None reported job discrimination. CONCLUSION Breast cancer survivors in this study encountered some problems in returning to work, mainly linked to the sequelae of their disease and its treatment rather than to discrimination by employers or colleagues.

Raltitrexed in the treatment of elderly patients with advanced colorectal cancer: an active and low toxicity regimen

In spite of the high prevalence of advanced colorectal cancer in the elderly, we have little data on the efficacy and toxicity of chemotherapy in this age group. Raltitrexed is a thymidylate synthetase inhibitor with known activity in the treatment of advanced colorectal cancer. The objective of this study was to analyse the efficacy and tolerance of raltitrexed in elderly patients with advanced colorectal cancer. 92 patients diagnosed with advanced colorectal cancer aged >or=70 years were entered into the study. Raltitrexed was given at a dose of 3 mg/m(2) once every 3 weeks for a minimum of three cycles. A total of 511 cycles were given with a median of five cycles per patient. 20 out of the 90 patients evaluable for response achieved a partial response (PR) (22%, 95% Confidence Interval (CI): 17-36%), 43 (48%) remained stable and 27 showed progression (30%). The mean duration of response was 24 weeks and the progression-free interval was 15 weeks. The overall median survival was 41 weeks. 31 patients (39%, 95% CI: 28-50%) experienced a clinical benefit (improvement of the performance status without a worsening of symptoms or relief of symptoms without a worsening of the performance status). The main toxicities were gastrointestinal and haematological. 12 patients (13%) developed grade 3-4 side-effects: 7 had nausea/vomiting (8%), 6 a transaminase increase (7%), 4 asthenia (4%), 3 diarrhoea (3%), 2 neutropenia (2%), 2 anaemia (2%) and 1 thrombocytopenia (1%). Three toxic deaths occurred (3%). The group of patients with a creatinine clearance <or=1.08 ml/s was found to have a higher risk of developing grade 3-4 toxicity compared with those with adequate renal function (8/18 versus 4/72; P<0.001). In conclusion, raltitrexed is an active, convenient and low toxicity treatment for the elderly with advanced colorectal cancer. However, it must be used cautiously in elderly patients with a creatinine clearance <or=1.08 ml/s since they are at a higher risk of suffering grade 3-4 toxicity.

Phase II Trial of Gemcitabine and UFT Modulated by Leucovorin in Patients with Advanced Pancreatic Carcinoma

Use of chemotherapy for advanced pancreatic carcinoma (APC) pursues a palliative objective. Gemcitabine is active against this tumor and shows in vitro synergism with 5‐fluorouracil. UFT is a combination of tegafur (a prodrug of 5‐flouorouracil) and uracil that can be given orally. The administration of UFT for several weeks may simulate the effects of a continuous infusion of 5‐fluorouracil. The objective of the current study was to assess the efficacy and toxicity of the combination gemcitabine‐UFT‐leucovorin in the treatment of APC.

Treatment of patients with advanced gastric carcinoma with the combination of etoposide plus oral tegafur modulated by uracil and leucovorin: A phase II study of the ONCOPAZ Cooperative Group

Both the biochemical modulation and the continuous administration of 5‐fluorouracil (5‐FU) have achieved promising results in patients with gastric carcinoma. Conversely, several studies on gastric carcinoma have demonstrated that the combination of etoposide (VP‐16), leucovorin (LV), and 5‐FU (ELF) is efficacious and moderately toxic. UFT is a combination of uracil and tegafur (ftorafur) in a 4:1 molar ratio. It can be administered orally for several weeks, thus stimulating the effects of a continuous infusion of 5‐FU. Its combination with LV increased the efficacy of UFT. We conducted a Phase II study on patients with gastric carcinoma using the combination VP‐16‐LV‐UFT. This combination is administered mainly orally (p.o) and could yield a good response rate and low toxicity.

Sequential therapy in advanced non-small-cell lung cancer with weekly paclitaxel followed by cisplatin—gemcitabine—vinorelbine. A phase II study

OBJECTIVES New effective therapies are needed to improve the outcome of patients with advanced non-small-cell lung cancer (NSCLC). The aim of this study was to assess the response rate and survival obtained with a sequential regimen of chemotherapy. PATIENTS AND METHODS Patients with newly diagnosed stage IIIb-IV NSCLC were included. They all had measurable disease and a good performance status (0-2 in the Eastern Cooperative Oncology Group scale). Chemotherapy consisted of weekly paclitaxel 150 mg/m2 x 6, followed two weeks later by cisplatin 100 mg/m2 on day 1, gemcitabine 1,000 mg/m2 on days 1 and 14, and vinorelbine 25 mg/m2 on days 1 and 14 (CGV). CGV was administered every 28 days for a maximum of six courses. RESULTS Fifty-two patients were included, 19 (37%) with stage IIIb and 33 (63%) with stage IV disease. After therapy with weekly paclitaxel. 29 partial responses were obtained (56%, 95% confidence interval (95% CI): 38%-67%), whereas 15 patients had stable disease (29%) and eight had a progression (15%). After CGV, there were four complete remissions (8%) and 24 partial responses (46%), for an overall response rate of 54% (95% CI: 37%-65%). Eight patients had stable disease (15%) and 16 had a progression (31%). No patient progressing after paclitaxel responded to CGV, whereas 5 out of 15 patients with stable disease reached a partial response with CGV (33%). On the contrary, 5 out of 29 patients with a partial response to paclitaxel progressed after CGV (17%). Median survival has not been reached after a median follow-up of 14 months. Median time to progression was nine months. Fifty-six percent of patients remain alive at one year. Two hundred eighty-nine courses of paclitaxel and 170 of CGV were given, with a median of 5.5 and 3.4 per patient, respectively (ranges 2-6 and 0-6. respectively). WHO grade 3-4 toxicities for paclitaxel were: neutropenia in two patients (4/) and peripheral neuropathy in five (10%). Two patients had allergic reactions requiring paclitaxel withdrawal, whereas four (8%) had hyperglycemia >250 mg/ml. Grade 3-4 toxicities for CGV were: neutropenia in ten patients (20%), peripheral neuropathy in six (12%), anemia in four (8%), nausea/vomiting in five (10%). thrombocytopenia in two (4%), and fatigue in four (8%). CONCLUSION Our results suggest that sequential chemotherapy with weekly paclitaxel followed by CGV is highly active in patients with advanced NSCLC and has an acceptable toxicity. This schedule deserves further evaluation in a phase III study.

Comparison of two antibiotic regimens (piperacillin plus amikacin versus ceftazidime plus amikacin) as empiric therapy for febrile neutropenic patients with cancer.

A total of 170 febrile episodes in neutropenic patients with cancer were randomly assigned to be treated with piperacillin-amikacin or ceftazidime-amikacin. The overall response rates were similar in both groups (68 and 65%, respectively). Response rates for clinically or microbiologically documented episodes were 54.5% for piperacillin-amikacin and 58.8% for ceftazidime-amikacin. Response rates for gram-negative bacillary infections were 65 and 73%, respectively. There was also no difference for gram-positive infections (31 and 50%, respectively). The toxicities were also comparable and consisted of skin rashes, hypokalemia, and diarrhea. Vancomycin was added if the fever persisted 72 h after the beginning of therapy; it increased the response rates to 94% when used with piperacillin-amikacin and 92% when used with ceftazidime plus amikacin. Our results suggest that the combinations show similar global efficacies in the treatment of febrile episodes in cancer patients.

Experience of Oncopaz Cooperative Group with Oral Fluoropyrimidines in Tumors of the Stomach, Lung, Head and Neck, and Breast

The Oncopaz Cooperative Group designed a chemotherapy regimen to modulate UFT (Tegafur and Uracil) with leucovorin. The regimen consisted of a high intravenous dose of leucovorin, followed by oral UFT and oral leucovorin twice daily for 14 days. Based on the promising results obtained with this regimen in patients with advanced colorectal cancer, the Oncopaz group performed several phase II trials using this combination with other drugs to treat advanced gastric, lung, head and neck, and breast cancers. When combined with etoposide in gastric cancer, the regimen was shown to be active and well tolerated. However, when used with cisplatin to treat non-small cell lung cancer, a low response rate and high toxicity precluded its recommendation for further study. The addition of carboplatin in the treatment of head and neck cancer demonstrated moderate activity with low toxicity. In an ongoing trial of advanced breast cancer, preliminary results indicate that the combination of idarubicin, UFT, and leucovorin is active, with moderate, primarily hematologic toxicity. Trials of new combinations are warranted to take advantage of the pharmacokinetic properties and oral bioavailability of UFT and leucovorin.