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Hereditary non-polyposis colorectal cancer (HNPCC) represents 1-3% of all colorectal cancers. HNPCC is caused by a constitutional defect in a mismatch repair (MMR) gene, most commonly affecting the genes MLH1, MSH2 and MSH6. The MMR defect results in an increased cancer risk, with the greatest lifetime risk for colorectal cancer and other cancers associated to HNPCC. The HNPCC-associated tumor phenotype is generally characterized by microsatellite instability (MSI) and immunohistochemical loss of expression of the affected MMR protein. The aim of this study was to determine the sensitivity of IHC for MLH1, MSH2 and MSH6, and MSI analysis in tumors from known MMR gene mutation carriers. Fifty-eight paired normal and tumor samples from HNPCC families enrolled in our high-risk colorectal cancer registry were studied for the presence of germline mutations in MLH1, MSH2 and MSH6 by DGGE and direct sequencing. MSI analysis and immunostaining for MLH1, MSH2 and MSH6 were evaluated. Of the 28 patients with a real pathogenic mutation, loss of immunohistochemical expression for at least 1 of these MMR proteins was found, and all except 1 have MSI-H. Sensitivity by MSI analysis was 96%. IHC analysis had a sensitivity of 100% in detecting MMR deficiency in carriers of a pathogenic MMR mutation, and can be used to predict which gene is expected to harbor the mutation for MLH1, MSH2 and MSH6. This study suggests that both analyses are useful for selecting high-risk patients because most MLH1, MSH2 and MSH6 gene carriers will be detected by this 2-step approach. This practical method should have immediate application in the clinical work of patients with inherited colorectal cancer syndromes.

Oxaliplatin (L-OHP), irinotecan (CPT-11) and 5-fluorouracil (5-FU) have shown their efficacy in metastatic colorectal cancer. The synergism of these drugs has been demonstrated in vivo and in vitro. The aim of this study was to determine the recommended dose of the triple combination of L-OHP, CPT-11 and CI 5-FU for a further phase II study. Eighteen patients received the study treatment in four dose levels. The male:female ratio was 15:3 and the median age was 51.6 years (range 30-71). The type of tumor was colon in eight patients, rectum in four and other locations in six patients. The treatment was repeated every 2 weeks, at the fixed dose of L-OHP, 85 mg/m, and escalated doses of CPT-11 and 48-h infusion 5-FU of 100/2000, 100/2250, 125/2250 and 150/2250 mg/m. Only one previous treatment for the advanced disease was permitted. Patients received a median of 8 cycles (range 1-26) and a total of 152 cycles were administered. Dose intensity administered at dose level L-OHP 85 mg/m, CPT-11 150 mg/m and 5-FU 2250 mg/m was 95, 92 and 95% for L-OHP, CPT-11 and 5-FU, respectively. One patient in level 2 and one patient in level 4 presented dose-limiting toxicity that was not confirmed in the three required additional patients by level. The anti-tumor activity was assessed in nine patients: seven partial responses, one stable disease and one progressive disease. The maximum-tolerated dose was not reached, and thus the recommended dose for this combination schedule is L-OHP, 85 mg/m, CPT-11, 150 mg/m and 5-FU, 2250 mg/m 48-h continuous infusion, the same doses that were recommended for the drugs when administered in combination therapy of L-OHP + 5-FU or CPT-11 + 5-FU. A phase II study in first-line treatment of patients with metastatic colorectal cancer with this dose regimen is ongoing.

Pancreatic, gastric, and colorectal cancers are major causes of morbidity and mortality worldwide. When curative surgical resection is not an option, these malignancies tend to respond very poorly to chemotherapy and carry a dismal prognosis. There is, therefore, an urgent need for novel treatment strategies for these cancers. Great strides have been made in colon cancer treatment with the recent introduction of several novel agents, including capecitabine, irinotecan, and oxaliplatin either alone or in combination regimens. Treatment of advanced colon cancer, however, remains essentially palliative, and treatment-related toxicity remains a significant problem. The treatment of advanced gastric and pancreatic cancer has also seen the introduction of new agents, such as gemcitabine and irinotecan; however, the impact of these agents on survival has been small, and toxicity continues to be a major obstacle. The search for new chemotherapeutic agents and treatment strategies will need to focus on improving outcomes and safety and tolerability profiles. To date, several new agents have shown promise, including pemetrexed, G17DT, bevacizumab, and other targeted agents. Further research into their optimal use either alone or in combination regimens should be a priority.

Background: The purpose of this study was to determine the relative efficacy of doxorubicin versus methotrexate in combination with intravenous cyclophosphamide and 5-fluorouracil (FAC versus CMF) as adjuvant chemotherapy for operable breast cancer., Patients and Methods: Over a 4-year period, 985 women undergoing curative surgery for breast cancer (T1-3 N0-2 M0, stage I-IIIA, UICC) from nine hospitals were stratified with respect to axillary node involvement (node positive versus node negative) and randomized to receive either FAC (500/50/500/m(2)) every 3 weeks for six cycles or CMF (600/60/600/m(2)) every 3 weeks for six cycles., Results: The relative dose intensities of FAC and CMF were 87% and 85% of planned doses, respectively. Unadjusted data indicated a non-significant trend towards better results with FAC. In the prospectively formed subset of node-negative patients, disease-free survival and overall survival were statistically superior in the FAC treatment arm (P = 0.041 and 0.034, respectively), but this advantage was not seen in the subset of node-positive patients, probably because of a difference in the percentage of patients with four or more positive nodes. Adjusting data for size of treatment effect and potential interactions (number of positive nodes, tumor size, treatment center), the overall relative risk (RR) of disease recurrence and death were significantly lower with FAC treatment (RR 1.2, P = 0.03, and RR 1.3, P = 0.05, respectively). This result was mainly due to the difference observed in the node-negative patient population. Toxicity was mild: FAC induced more alopecia, emesis, mucositis and cardiotoxicity; this last was of clinical concern, but was infrequent and manageable. CMF induced more conjunctivitis and weight gain. There were no toxic deaths., Conclusions: Doxorubicin in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil is superior to methotrexate in combination with day 1 i.v. cyclophosphamide and 5-fluorouracil as adjuvant chemotherapy for operable breast cancer. A treatment effect is particularly evident in the node-negative patients. Although the clinical toxicity of FAC is greater than that of CMF, the levels were manageable and clinically acceptable.

This article summarises the progress that has been made in the adjuvant treatment of colorectal cancer over the last decade. In view of the consequent improvements in recurrence rates and in overall survival, the development of effective adjuvant treatments for colorectal cancer is considered as one of the most important to be made in clinical oncology over the last decade. Treatment recommendations based on evidence-based data and on expert opinions are summarised in this manuscript. However, a consensus cannot be reached on all aspects of treatment because of data that is currently emerging that will influence clinical practice and because of the many ongoing clinical trials. Those involved in the treatment of colorectal cancer should therefore be encouraged to continue to provide optimal patient care and to participate in well designed clinical trials in order to increase the evidence upon which they can base their clinical judgements and in order to make further progress.

HNPCC is an autosomal dominantly inherited cancer-susceptibility syndrome that confers an increased risk for colorectal cancer and endometrial cancer at a young age. It also entails an increased risk of a variety of other tumors, such as ovarian, gastric, uroepithelial and biliary tract cancers. The underlying pathogenic mutation lies in 1 of the 5 known DNA MMR genes (MSH2, MLH1, PMS1, PMS2 and MSH6). We screened a total of 140 individuals from 56 Spanish families with suspected HNPCC for mutations in the DNA mismatch repair genes MLH1 and MSH2, using DGGE and direct DNA sequencing. Families were selected on the basis of a history of HNPCC-related tumors or the occurrence of other associated tumors in members besides the index case affected with colorectal cancer. We detected 14 definite pathogenic germline mutations, 9 in MLH1 and 5 in MSH2 in 13 unrelated families selected by the Amsterdam criteria and Bethesda guidelines (1 family carries 2 mutations) and 3 missense mutations in 3 unrelated families selected by the Amsterdam criteria. Among the 17 germline mutations noted in the Spanish cohort, 10 are novel, 7 in MLH1 and 3 in MSH2, perhaps demonstrating different mutational spectra in the Spanish population, where no founder mutation has been identified. Based on our results, we suggest that in the Spanish population not only HNPCC families fulfilling the Amsterdam criteria but also those following Bethesda guidelines should undergo genetic testing for MSH2 and MLH1 mutations., (Copyright 2002 Wiley-Liss, Inc.)

Germline mutations in the MLH1 and MSH2 genes, account for the majority of HNPCC families. We have screened such families from Spain by using DGGE analysis and subsequent direct sequencing techniques. In eight families we identified six novel MLH1 and two novel MSH2 mutations comprising one frame shift mutation (c.1420 del C), two missense mutations (L622H and R687W), two splice site mutations (c.1990-1 G>A and c.453+2 T>C and one nonsense mutation (K329X) in the MLH1 gene as well as two frame shift mutations (c.1979-1980 del AT and c.1704-1705 del AG) in the MSH2 gene. Our analysis contributes to the further characterization of the mutational spectrum of MLH1 and MSH2 genes in HNPCC families., (Copyright 2001 Wiley-Liss, Inc.)

Thirty-four patients with metastatic breast cancer (MBC) who had progression of disease after high-dose chemotherapy (HDCT) with peripheral blood progenitor cell support (PBPC) had methotrexate, uracil and tegafur (UFT), and leucovorin (MUL) therapy administered: methotrexate administered intramuscularly in combination with UFT given orally and leucovorin given orally. All patients had received extensive prior chemotherapy including a high-dose regimen with PBPC support. Two complete responses (CR) and 11 partial responses (PR) were observed (objective response rate: 13/34 or 38%, 95% confidence interval 22-56%). Seven additional patients had stable disease (SD), 4 of whom (12% of the total population) of 6 months or longer duration, with the clinical benefit rate (CR + PR + SD of at least 6-month duration) reaching 50%. Median follow-up was 38 months, and the median time to progression and the median overall survival time from the start of MUL were 5.5 and 11 months, respectively. Toxicity was mainly gastrointestinal. Eight patients (24%) had World Health Organization grade II or greater diarrhea and/or enteritis and, consequently, the UFT dose was reduced. Emesis was mild and easily manageable with thiethylperazine given orally. The regimen did not produce significant myelosuppression or alopecia. In conclusion, patients with MBC retain chemosensitivity even when they progress after HDCT/PBPC and can be treated again with chemotherapy. MUL is active and well tolerated in patients with MBC progressing after HDCT. Further studies with this regimen, as salvage chemotherapy or as maintenance chemotherapy after HDCT/PBPC, would appear to be warranted.

Purpose: To determine the maximum-tolerated dose and the antitumor activity of a combination of paclitaxel, cisplatin, and gemcitabine in advanced transitional-cell carcinoma (TCC) of the urothelium., Patients and Methods: Patients with measurable, previously untreated, locally advanced or metastatic TCC and with Eastern Cooperative Oncology Group performance status < or = 2 and creatinine clearance > or = 55 mL/min were eligible. Cisplatin was given on day 1 at a fixed dose of 70 mg/m(2). Paclitaxel and gemcitabine were given on days 1 and 8 at increasing dose levels. Cycles were repeated every 21 days to a maximum of six cycles., Results: Sixty-one patients were registered. In phase I, 15 patients were entered at four different dose levels. Dose-limiting toxicity consisted of early onset (after the first cycle) grade 2 asthenia (two of six patients) and grade 3 asthenia (one of six patients) at dose level 4. A paclitaxel dose of 80 mg/m(2) and gemcitabine 1,000 mg/m(2) was recommended for phase II, and 46 additional patients were entered at this level for a total of 49 patients. Main nonhematologic toxicity was grade 2 asthenia in 18 patients, with early onset in five patients, and grade 3 in four patients. Grade 3/4 neutropenia and thrombocytopenia occurred in 27 (55%) and 11 (22%) patients, respectively. Overall, febrile neutropenia was seen in 11 patients, and one toxic death occurred because of neutropenic sepsis. The combination was active at all dose levels. In total, 58 of 61 eligible patients were assessable for response; 16 complete responses (27.6%) and 29 partial responses (50%) were observed for an overall response rate of 77.6% (95% confidence interval, 60% to 98%). The median survival time (MST) available for the phase I part of the study is 24.0 months. MST has not been reached for the whole group with the current follow-up., Conclusion: This combination of paclitaxel, cisplatin, and gemcitabine is feasible and highly active in patients with advanced TCC of the urothelium. Further evaluation of this regimen in patients with TCC is warranted.

Purpose: To evaluate the anti-tumour activity and tolerance of the combination of paclitaxel plus vinorelbine in metastatic breast cancer (MBC) patients previously treated with anthracyclines., Patients and Methods: Fifty-six MBC patients who have had at least one previous anthracycline-containing chemotherapy regimen were enrolled in this phase II trial. Patients received paclitaxel (135 mg/m2 over one-hour infusion) and vinorelbine (30 mg/m2) both on day 1 of each three-week course of therapy (maximum eight courses or until disease progression was evident)., Results: Six complete and nineteen partial responses were observed among the fifty-four assessable patients (response rate of 46%, 95% CI: 33%-60%). Responses were observed in all disease sites and in all subsets of patients. The response rates when paclitaxel plus vinorelbine were used as first, second and third-line chemotherapy for metastases were 67%, 41% and 35%, respectively. The response rate among anthracycline-refractory patients was 46% (6 of 13). Median time to progression in the overall patient group was 28 weeks. The main toxicities (CTC grade 2 or more) were alopecia, myelosuppression and peripheral neuropathy (85%, 46% and 19% of patients, respectively). Nine patients (17%) had neutropenic fever in fifteen of the three hundred twenty-eight courses administered (5%)., Conclusions: The combination of paclitaxel and vinorelbine on day 1 every three weeks is active in MBC patients with prior anthracycline exposure. The regimen is safe, well tolerated and convenient for the patients.

In some tumors, defects in mismatch repair enzymes lead to errors in the replication of simple nucleotide repeat segments RER+ tumors. This condition is commonly known as microsatellite instability (MSI) because of the frequent mutations of microsatellite sequences. Although the MSI phenotype is well recognized in some colon, gastric, pancreatic, and endometrial cancers, reports of MSI in breast cancer are inconsistent. The purpose of this study was to determine the presence of MSI in breast cancer and to correlate its occurrence with clinicopathological parameters, including expression of estrogen and progesterone receptors. We analyzed the status of 10 different microsatellite loci (mono- and dinucleotide repeats). In this study, microsatellite size patterns were compared in 88 paired breast-cancer/peripheral-blood DNA samples. Fluorescent polymerase chain reaction (PCR) for typing microsatellites coupled with DNA fragment analysis in an automated DNA sequencer was applied. MSI in at least two microsatellite markers was observed in 6 out of 88 (7%) of the cases, all belonging to Stage II or III. These MSI data were analyzed using a range of clinicopathological parameters; no correlation between MSI and histopathological characteristics were found. A significant correlation was observed between MSI and negative expression of both estrogen and progesterone receptors (P<0.02), indicating a possible relationship between specific genetic changes at these microsatellite regions and hormonal deregulation in the progression of breast cancer.

Background and Goals: The purpose of this study was to characterize the biologic determinants that affect the behavior of invasive lobular carcinoma of the breast., Material and Methods: A prospectively accrued data base containing 9,619 breast cancer cases was queried for specific pathological features. From this data base, 390 patients with invasive lobular carcinoma of the breast treated and followed at any of these three centers: San Carlos Hospital, Doce de Octubre Hospital or The Jimenez Diaz Foundation in Madrid (Spain) were reviewed and results, in terms of overall survival and disease-free survival were recorded for a long-term follow-up of 206 months (17 years)., Results: The parameters that showed an important statistical influence on survival were the stage at diagnosis, the tumor size and nodal status, as well as the tumor grade. Age showed a limited influence, and multicentricity, or the type of surgical procedure had no statistical impact on survival., Conclusions: Our analysis specifies the clinico-pathological features that influence the prognosis of invasive lobular carcinoma of the breast, and confirms that conservative therapy may be an appropriate treatment for this type of cancer.

Immunohistochemical reactivity for p53 protein is common in various human malignancies. Increased intracellular concentration of p53, which is frequently, but not systematically, related to p53 mutation, has been proposed to be associated with poor prognosis in some tumor types. In colorectal cancer, this significance is still a matter of debate. To directly investigate the relationship between prognosis and p53 alterations, we screened a series of 72 colorectal carcinomas for overexpression and mutation of the p53 gene. Mutations in exons 5-9 of the p53 gene were assayed by single-strand conformation polymorphism and direct DNA sequencing, whereas p53 protein accumulation was detected in 10-microm frozen tissue by immunostaining using 2 different monoclonal antibodies (PAb 1801 and DO7). Thirty-six tumors (50%) showed p53 overexpression. Nineteen of the 36 tumors which contained high levels of p53 protein were found to have missense point mutations. Using a multivariate survival analysis, stage, differentiation, p53 immunoreactivity and p53 mutation emerged as risk factors, but only the stage was significant. In univariate analysis, stage, differentiation and p53 immunoreactivity were significant prognostic indicators, while p53 mutation was at the borderline of significance.

Thirty-three metastatic breast cancer patients with prior chemotherapy (adjuvant alone, 9 patients; chemotherapy for metastatic disease alone, 13 patients; chemotherapy for both, 11 patients) received paclitaxel (Taxol) 135 mg/m2 over 1 h followed by vinorelbine (Navelbine) 30 mg/m2 over 10 minutes on day 1 every 3 weeks. All patients had contraindications to receive anthracycline therapy (primary resistance, 10 patients; dose reaching the maximum recommended dose and/or myocardiopathy, 23 patients). Twenty-eight patients had previously received anthracyclines, and the remaining 5 had received prior CMF (cyclophosphamide, methotrexate, fluorouracil). The combination of paclitaxel plus vinorelbine was given as first-line chemotherapy for metastatic disease to 9 patients and as second- or third-line to the remaining 24 patients. The mean number of metastatic sites was 2 (range 1-5). Twenty-two patients had visceral involvement. Overall, 3 complete and 13 partial responses were observed among the 33 patients (objective response rate 48.5%, 95% confidence interval 31% to 66.5%). The response rate in patients receiving the regimen as first-line chemotherapy was 67% (6/9 patients), compared to 42% (10/24) in those receiving the regimen as second- or third-line chemotherapy. Primary anthracycline-resistant patients showed a response rate of 60% (6/10), whereas the remaining patients had a response rate of 43.5% (10/23). The main toxicities were grade 3 alopecia (92%), grade 3-4 neutropenia (28%), neutropenic fever (16%), grade 1-2 peripheral neuropathy (44%), arthralgias-myalgias (32%), and hypersensitivity reactions (8%). Phlebitis was a significant clinical problem in patients receiving the drugs through a peripheral vein.

The oral fluoropyrimidines have proved to be active in colorectal cancer in Japan and, recently, in the United States and Europe. Continuous oral administration simulates protracted fluorouracil (5-FU) continuous intravenous infusion. The purpose of this trial was to evaluate the tolerability and potential advantages of oral treatment for colorectal cancer in the elderly. The main inclusion criterion was age over 72 years. Patients were treated with UFT (tegafur plus uracil) 400 mg/24 hours (fixed doses) continuously plus folinic acid 45 mg/24 hours until toxicity. If grade 3 or 4 toxicity appeared, treatment was stopped until recovery. From September 1994 to November 1996, 126 patients were included. For the analysis in November 1996, 77 patients were evaluable for response, toxicity, and survival. The patients, including 34 women and 43 men, had a median age of 74 years (range, 72 to 82 years of age). The Karnofsky performance status was 60% to 80% for 41 patients and 90% to 100% for 36 patients. Liver metastasis was present in 48% of the cases, and 42% were locoregional and peritoneal. Toxicity was mild, with only one patient having grade 3 thrombocytopenia, 11 (14%) grade 3 or 4 nausea/vomiting, seven (9%) grade 3 or 4 diarrhea, and one grade 3 mucositis. Four patients (5%) had complete responses and nine (11.6%) partial responses, for an objective response rate of 16.9% (95% confidence interval, 9% to 27%). Twenty-two patients (28.6%) showed no change. The number of patients in whom disease did not progress (ie, patients with complete plus partial responses plus those with stable disease) was 35 (45.4%) (95% confidence interval, 34% to 57%). With a maximum follow-up of 24 months, the median actuarial survival is 14.4 months. The number without disease progression and the median survival in this preliminary analysis suggests that this schedule is a moderately effective, comfortable, treatment with only mild toxicity, that can be recommended for use in the elderly, and it warrants further study.

This study compared the activity and toxicity of fluorouracil (5-FU)/ cisplatin with the combination tegafur and uracil (UFT)/cisplatin in the neoadjuvant treatment of locally advanced-stage III or IV (MO)-head and neck cancer. A total of 67 patients were randomly assigned to treatment with cisplatin 100 mg/m2 on day 1 followed by either a continuous infusion of 5-FU 1,000 mg/m2/day on days 2 through 6 (group 1) or oral administration of UFT 300 mg/m2/day on days 2 through 20 (group 2). Both treatments were repeated every 21 days for four cycles. Responding patients received locoregional standard radiotherapy (50 to 70 Gy) after chemotherapy. Group 1 was comprised of 34 patients, 30 of whom were men, with a median age of 57.5 years; 79% of this group had a Karnofsky performance status of 90% to 100%; 70% had a squamous and 29% an undifferentiated histology. The majority (85%) had stage IV disease. Of the 33 patients in group 2, 29 were men. The median age was 56 years. Most (88%) had a performance status of 90% to 100%. More patients had a squamous than an undifferentiated histology (82% vs 18%) and most (88%) had stage IV disease. Overall response in group 1 was 73% (21% complete) compared with 79% (18% complete) in group 2. At a median follow-up of 84 months, no significant differences have emerged in overall survival, 15 vs 37 months, or time to progression, 8.5 vs 14.5 months, for groups 1 and 2, respectively. Toxicity was also similar, except for phlebitis, which occurred significantly more often in group 1 (71% vs 9%). Cisplatin/UFT was as effective as the classic cisplatin/5-FU regimen and has the advantages of outpatient oral administration and a lower incidence of phlebitis.

Twenty-four patients with metastatic breast cancer that had progressed after high-dose chemotherapy with peripheral blood progenitor cell (PBPC) support were given intramuscular methotrexate in combination with oral UFT (tegafur and uracil) and oral leucovorin (the MUL regimen). Of the total treated, 21 patients are currently evaluable for response and toxicity. All patients had received extensive prior chemotherapy, including a high-dose regimen with PBPC support. Of the 21 assessable patients, 8 obtained either a complete response (1) or partial response (7), for an overall objective response rate of 38%. Another 7 patients had stable disease for 3 or more months. Therefore, the MUL regimen was able to stop disease progression for 3 or more months in nearly 75% of patients. The median time to progression and median overall survival from the start of MUL were 6 and 9 months, respectively. The toxicity was mainly gastrointestinal; 6 patients (29%) had World Health Organization grade 2/3 diarrhea, leading to a UFT dose reduction. Emesis was mild and easily manageable with thiethylperazine. In conclusion, MUL chemotherapy is active and well tolerated in patients with metastatic breast cancer in progression after high-dose chemotherapy. Further studies with this regimen, either as salvage chemotherapy or as maintenance chemotherapy after high-dose chemotherapy with PBPC, are warranted.

A group of 90 breast cancer patients undergoing chemotherapy were assessed prospectively to estimate the prevalence of acute (post-treatment) and anticipatory emesis in the 1990s. For this purpose, two protocols of chemotherapy were analysed separately: cyclophosphamide/methotrexate/5-fluorouracil (CMF) and 5-fluorouracil/doxorubicin/cyclophosphamide (FAC). All patients were treated with antiemetic therapy, which included one corticoid plus ondansetron (in the FAC regimen), or one corticoid plus thiethylperazine (in the CMF regimen). For at least one cycle of chemotherapy 86.1% and 91.7% patients in the FAC protocol presented vomiting and nausea respectively: 11.1% had anticipatory vomiting and 30.6% had anticipatory nausea. In the CMF protocol, 79.6% had post-chemotherapy vomiting and 71.7% had post-chemotherapy nausea associated with at least one cycle. In this group, 7.4% had anticipatory vomiting and 16.6% had anticipatory nausea. A high proportion of patients suffered anticipatory anxiety in both groups (75% in FAC, 74.1% in CMF). The stimuli most frequently associated with the appearance of anticipatory emesis were olfactory stimuli and cognitive stimuli. In summary, as a result of the advances made in antiemetic control during the last decade, the severity of chemotherapy-induced emesis seems to have significantly decreased, but the prevalence of these symptoms along the course of the treatment still remains high.

This multicentre, randomised, double-blind study was designed to compare the anti-emetic efficacy and safety of single oral doses of dolasetron mesilate with that of the approved oral, multiple-dose regimen of ondansetron in 399 cancer patients receiving moderately emetogenic chemotherapy. Single oral doses of 25, 50, 100 or 200 mg of dolasetron mesilate were administered 1 h prior to the initiation of moderately emetogenic chemotherapy. Multiple doses of ondansetron (8 mg x 3 or 8 mg x 4) capsules, or matching placebo for patients randomised to dolasetron, were given 1.5 h before and 6.5, 14.5 and 22.5 h after the start of chemotherapy (total dose = 32 mg). Efficacy was evaluated for 24 h after the initiation of chemotherapy. The most frequently used moderately emetogenic chemotherapeutic agents included cyclophosphamide, doxorubicin and carboplatin (28.4, 23.1 and 20.6% of patients, respectively). A statistically significant (P < 0.001) linear dose-response relationship was observed over the entire dolasetron dosage range for all efficacy parameters. Complete response rates were 45.0, 49.4, 60.5 and 76.3% for 25, 50, 100 and 200 mg dolasetron mesilate, respectively, and 72.3% of ondansetron patients. A single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to ondansetron for all efficacy parameters and patient satisfaction was high. Overall, there were no significant differences in the incidence of adverse events between any of the dolasetron mesilate doses, or between dolasetron and ondansetron. Headache was most frequently reported (approximately 15% for each drug). No clinically important changes in vital signs or clinical laboratory parameters were observed with either drug. In conclusion, a single oral 200 mg dolasetron mesilate dose was therapeutically equivalent to multiple-dose ondansetron in the prevention of emesis and nausea following moderately emetogenic chemotherapy.

This multicentre, double-blind, double-dummy, randomised trial was designed to compare the efficacy and safety of single intravenous doses of dolasetron mesilate and granisetron in the prevention of acute emesis and nausea due to high-dose (> or = 80 mg/m2) cisplatin. Single intravenous doses of 1.8 or 2.4 mg/kg of dolasetron mesilate or 3 mg of granisetron hydrochloride were administered in a volume of 50 ml over a 5-min period, beginning 30 min prior to cisplatin (> or = 80 mg/m2) administration. The number and timing of emetic episodes, time to administration of escape anti-emetic medication, severity of nausea by visual analogue scale (VAS), and safety were monitored for 24 h after the start of cisplatin-containing chemotherapy. Investigators' evaluations of overall efficacy and patients' satisfaction with therapy were recorded at the end of the 24-h study period. Of the 474 patients evaluable for efficacy, complete responses were achieved by 54, 47 and 48% of patients given dolasetron mesilate 1.8 mg/kg, dolasetron mesilate 2.4 mg/kg and granisetron, respectively. Statistically, treatment groups had comparable complete and complete plus major responses, times to first emesis, and use of escape medication; patient maximum nausea severity and treatment satisfaction ratings; and physician nausea severity and overall efficacy assessments. For the majority of efficacy endpoints, 1.8 mg/kg dolasetron mesilate produced numerically superior responses compared with the 2.4 mg/kg dose. Gender and prior chemotherapy were significant predictors of complete response; males and chemotherapy-naive patients had higher responses. The overall incidences of adverse events were comparable among the treatment groups; headache and diarrhoea were most common. In conclusion, 1.8 and 2.4 mg/kg of dolasetron mesilate and granisetron (3 mg) were equally effective in preventing nausea and vomiting induced by highly emetogenic cisplatin-containing chemotherapy. In addition, because no additional benefit was observed with 2.4 mg/kg of dolasetron mesilate and numerically greater responses were observed with the 1.8 mg/kg dose, the lower dose of 1.8 mg/kg is optimal for further clinical development.

A total of 37 men with epidermoid head and neck cancer whose disease had recurred following primary treatment (surgery and/or radiotherapy) received first-line chemotherapy with ifosfamide at i.v. doses of 3 g/m2 given daily on 3 consecutive days in combination with mesna (600 mg/m2 x 3 oral daily doses on days 1-3) every 3 weeks. In all, 7 patients showed a partial response and 2 patients achieved a complete response, for an overall objective response rate of 26% (9 of 35 eligible patients; 95% confidence interval, 12.5%-43%). Excluding the 5 early nontoxic deaths observed during the first 3 weeks of therapy, the objective response rate was 30% (9 of 30 patients; 95% confidence interval, 15%-49.5%). Responses were seen in lung metastases (2 patients), lymph nodes (2 patients), skin (3 patients), and cases of local recurrence (5 patients). The median duration of responses was 3 months (range, 2-5 months). The main side effects of ifosfamide were alopecia (83% of patients), emesis (80%), granulocytopenia (23%), and mild mucositis (20%). Two poor-risk patients suffered severe CNS complications that were probably related to treatment. Three patients died due to chemotherapy-related complications (2 patients with CNS toxicity and 1 patient with granulocytopenic sepsis). In conclusion, ifosfamide appears to be an active drug in epidermoid head and neck cancer and merits further evaluation in this disease.

The effects of oral and intravenous magnesium supplementation on cisplatin (CDDP)-induced hypomagnesemia were investigated in 41 patients treated with 100 mg/m2 CDDP. Patients were randomly allocated to receive no magnesium supplementation, intravenous magnesium supplementation (magnesium sulphate, 3 g before each CDDD administration) or oral magnesium supplementation (magnesium pidolate, 2 g orally every 8 hours on days 2 to 21 of each CDDP course) during the first 4 courses of CDDP treatment. Patients in both supplementation arms showed significantly higher magnesium levels than control patients from the second course on (oral magnesium arm) or from the third course on (intravenous magnesium arm). Three of the 9 patients (33%) in the intravenous magnesium arm and 4 of the 9 (44%) in the oral magnesium arm developed hypomagnesemia after the fourth course of CDDP, compared with 9 of the 10 (90%) unsupplemented patients. There were no magnesium-related side effects in patients on intravenous magnesium supplementation. Two patients treated with oral magnesium developed mild gastrointestinal symptoms (emesis and diarrhea), probably from magnesium therapy. Our study showed that both intravenous and oral magnesium supplementations appear to be safe and efficacious in the prevention of CDDP-induced hypomagnesemia. Since patients were not completely protected, and since the analysis was limited to the first four courses of chemotherapy, additional studies are needed to determine the best schedule of magnesium supplementation, especially in patients who receive more than four courses of CDDP chemotherapy.

The maintenance of the antiemetic efficacy of a combined protocol (intravenous methylprednisolone, oral thiethylperazine and oral amitriptyline) during six consecutive courses of adjuvant FAC chemotherapy (5-fluorouracil, doxorubicin, cyclophosphamide) was analysed in 107 female breast cancer patients who completed the six planned courses of treatment. A continuous decrease in complete (no vomiting episodes) and major protection rate (0-2 vomiting episodes) was evident during chemotherapy. Complete protection rate decreased from 62.6% in the first course to 48.6% in the sixth (P less than 0.05, chi 2 test). The respective figures for major protection rate were 76.6% and 58% (P less than 0.01, chi 2 test). These data, together with other from the literature, should be taken into consideration when reviewing the overall results of current antiemetic trials, which usually only mention the results obtained in the first course of chemotherapy.

The antitumor activity of carboplatin (400 mg/m2 intravenously every 4 weeks) in advanced breast cancer was evaluated in two consecutive trials enrolling patients with and without prior exposure to chemotherapy, respectively. All patients had measurable disease in at least one site. The first trial included patients who had received prior chemotherapy (adjuvant, neoadjuvant, or chemotherapy for metastatic disease). All but one of these patients had previously received doxorubicin-containing combinations. There were no objective responses among the first 14 evaluable patients, although 7 of them had stable disease, including 2 with minor responses. The second trial, carried out with patients who had no prior exposure to chemotherapy, is ongoing. Currently, 6 of 19 evaluable patients have obtained a complete (1) or partial (5) response to carboplatin, resulting in an overall response rate of 32%. In both studies, toxicity was mild, mainly consisting of emesis (88%), leukopenia (22%), and thrombocytopenia (12%). Thus, by standard criteria, carboplatin was not found to be active in breast cancer patients with prior exposure to chemotherapy. Preliminary results in patients without such exposure are encouraging, although additional patients are needed to confirm these data.

18 patients with advanced colorectal cancer entered a phase I-II study of high-dose 48 h continuous infusion 5-fluorouracil (5-FU) for 6 weeks. 7 patients were included at the first dose level (3 g/m2) and only 1 had serious toxicity (grade 3 diarrhoea and mucositis). 7 patients were included at the second dose level (3.5 g/m2). 6 had a good tolerance to treatment, while the remaining patient had grade 4 leukopenia. 4 patients received 4 g/m2: 3 had severe toxicity (grade 4 diarrhoea, myelosuppression, mucositis, central nervous system), such that the entry of new patients was stopped. Anti-tumour activity was seen in 33% (95% confidence interval 13-59%) of the overall population. Only patients who had not had previous chemotherapy responded to treatment (response rate in this subgroup [43%, 18-71%]). The optimal dose of 5-FU was 3.5 g/m2 weekly for six cycles.

A group of 132 patients with different disseminated solid tumors entered two consecutive antiemetic trials in which 5-fluorouracil given in a 120-h continuous infusion was the emetogenic stimulus. The purpose of the trials was to investigate the validity of Peroutka and Snyder's hypothesis. These authors suggested that CNS receptors other than the classical dopamine D-2 (e.g., histamine H-1 and muscarinic cholinergic receptors) were involved in emetic response. Hence, a combination of a phenothiazine (an antidopaminergic drug) with an antihistaminic or a tricyclic antidepressant (H-1 and muscarinic cholinergic blockers) was suggested to be possibly superior to phenothiazine alone against antineoplastic chemotherapy-induced vomiting. The first study showed the antiemetic superiority of a phenothiazine (thiethylperazine) over placebo but failed to show a superiority of the combination of thiethylperazine and an antihistaminic (diphenhydramine) over thiethylperazine alone. In contrast, the second study proved the superiority of the combination of thiethylperazine and a tricyclic antidepressant (amitriptyline) over thiethylperazine alone. In conclusion, tricyclic antidepressants - but not antihistaminics - potentiate the antiemetic activity of thiethylperazine against 5-fluorouracil-induced vomiting.

An extract from calf spleens, injected into mice, was found to inhibit their lymphocyte proliferative response to PHA-M and PWM in vitro. Despite the ability of the spleen extract to inhibit the response of lymphocytes to stimuli in vitro, no effect was observed on the repopulation of lymphocytes in the peripheral blood of sublethally irradiated mice. The data suggest that the spleen extract acts as a specific inhibitor of the innume competent cells since neither the precursors of lymphocytes nor other haematopoietic cells were affected.

Four cases of patients suffering from abdominal scar injuries (laparotomic eventration and colonic prolapse through the site of previous colostomy) associated with antineoplastic chemotherapy-induced emesis are presented. The hypothesis of emetic strain as the main cause of eventration of prolapse is discussed. The authors suggest the need of a routine prophylactic antiemetic treatment in patients submitted to abdominal surgery and subsequent antineoplastic chemotherapy in order to avoid these accidents.

This article presents a patient affected with epidermoid carcinoma of the soft palate who developed a dilated myocardiopathy with aortic embolism and fatal left cardiac failure after treatment with cisplatin (100 mg/m2, day 1) and 5-fluorouracil (1 g/m2/day i.v. days 2-6). The postmortem necropsy study showed diffuse interstitial edema and intracytoplasmic vacuolization of myocytes, without inflammatory changes. These findings were interpreted as acute toxic myocardiopathy, probably due to 5-fluorouracil treatment. Although the patient also received cisplatin, metoclopramide, allopurinol, thiethylperazine, and amitriptyline, before the onset of clinical symptoms, these drugs were not considered to play an important role in the production of this cardiopathy because of the dosage, necropsy findings, and lack of previous report.

Forty two ovarian cancer patients with residual disease after the first laparotomy were treated with the combination of cisplatin (80 mg/m2 day 1), adriamycin (50 mg/m2 i.v. day 2) and cyclophosphamide (500 mg/m2 i.v. day 2) (PAC). Forty women were considered evaluable for analysis, with an overall response rate (partial, plus complete responses) of 62.5%. Twelve patients (30%) obtained a complete response (histologically confirmed after second look surgery in 6 cases, surgical complete response, residual tumor completely resected in the second look-in 5 cases and maintained complete clinical remission without second look confirmation in 1 case). Main side effects were nausea and vomiting (90%), leukopenia (70%), mucositis (45%), and anemia (37%). Seventeen percent of the patients were free of disease at 60 months, after a median follow-up of 48 months. The prognostic factors that showed significant influence on survival were the Karnofski index (90-100 vs 80 or less), stage of the disease (II + III vs IV) and the volume of residual tumor after the first surgical procedure (less than or equal to 2 cms vs greater than 2 cms). Patients who achieved a complete remission have not reached the median 5 years survival, which was 10 months for the remaining patients. These results confirm the activity of PAC in ovarian cancer, mainly in those patients with residual tumor of less than 2 cms and good performance status.

Thirty-six patients suffering from disseminated epithelial tumors under treatment with Cisplatin alone or in combination with Vindesine entered a randomized, double-blind, cross-over study comparing the antiemetic activity of low-dose IV Metoclopramide (total dose: 0.8 mg/kg) with that of a combination of Metoclopramide (same schedule) plus Nortriptyline (2 X 50 mg PO) plus Thiethylperazine (3 X 10 mg IV). This combination was designed in an attempt to act simultaneously on gastrointestinal motility and neuroreceptors at central emetic pathways (Dopamine D-2, Histamine H-1 and muscarinic cholinergic). The antiemetic combination significantly reduces the median number of emetic episodes (p less than 0.01), the median volume of vomiting (p less than 0.01) and the median time of emesis (p less than 0.01) when compared with Metoclopramide alone and was also preferred by a significant number of patients (p = 0.0001) after passing through both antiemetic treatment arms being compared.