In many centres, the use of 5-fluorouracil (5-FU) combined with levamisole has become standard therapy for the treatment of patients with Dukes' C colon cancer. However, the role of levamisole remains unclear.

Two new drugs from two new chemotherapy compound families were developed concomitantly: Taxoter (docetaxel), a taxane derivate and CPT 11 (irinotecan) a topoisomerase inhibitor. Six phase I trials of Taxoter were performed. The limiting toxicity is neutropenia. The recommended dosage for phase II trial is 100 mg/m2 administered in 1 hour perfusion, every 21 days. Neutropenic fever is unfrequent. Other toxicities are mucositis, skin toxicity, hypersensibility reaction, weight gain and oedema. None of these toxicities were limiting. Six phase I studies were conducted to determine the maximum tolerated dose of CPT 11 (irinotecan). Two different schedules were studied: the weekly 30-90 minutes infusion and an infusion administered every three weeks in one day or daily over three or five consecutive days. The limiting toxicity of the weekly schedule is diarrhea. Therefore the recommended dosage is 100-150 mg/m2/week. While dose limiting toxicities in the three week schedule are diarrhea as well as neutropenia. The recommended dose is 350 mg/m2. Since diarrhea appeared to be the major problem in achieving high dose intensity with CPT 11, a dose escalation trial with drug support against diarrhea was performed. A recommended dosage of 500 mg/m2 is therefore described. These two drugs are under evaluation in a large spectrum of tumors. Their original mechanism of action suggests interesting therapeutic properties. Clinical studies in combination with other drugs are in progress to define the role of topoisomerase I inhibitors and taxane in cancer therapy.

Despite improvements in detection and management, metastatic breast cancer remains a leading cause of death among women in industrialized countries. Chemotherapy is the initial treatment of choice for patients with a negative estrogen receptor status, as well as for those with a positive estrogen receptor status who have failed to respond to endocrine treatment. Patients who fail on first-line chemotherapy become candidates for second-line salvage chemotherapy; the outlook for these patients is poor, and new active agents continue to be sought. Docetaxel (Taxotere; Rhône-Poulenc Rorer, Antony, France) is a semisynthetic taxoid that is an inhibitor of microtubule depolymerization. This new anticancer agent has been studied in an extensive phase II clinical trial program involving 162 patients with second-line metastatic breast cancer, 134 of whom were anthracycline resistant. Doses of 100 mg/m2 of docetaxel, administered over 1 hour every 3 weeks, produced an overall response rate of 50% (range, 41% to 58%) in 129 evaluable patients, with a median duration of 6 months (range, 2 to 17 months). The response rates achieved to date with docetaxel in anthracycline-resistant patients compare favorably with those produced by the best monotherapies currently available, and are equivalent to those achieved with current combination chemotherapy options. Docetaxel also was found to be highly effective in patients with a poor prognosis, having metastases in three or more organs (53%), and/or visceral sites of disease (47%). Furthermore, the overall response rate for docetaxel in the intent-to-treat population (42.5%) is superior to the response rate of either doxorubicin as second-line therapy (29.3%) or paclitaxel (Taxol; Bristol-Myers Squibb Oncology, Princeton, NJ) when used as first- or second-line therapy (29%) in metastatic disease. In conclusion, docetaxel appears to be a very effective therapeutic option for women with second-line metastatic breast cancer.

To determine the relationship between total dose intensity (TDI) of cisplatin/carboplatin, total dose intensity of all chemotherapy drugs (GDI) and median survival (MS) in stage III-IV ovarian cancer patients.

The management of breast cancer in older women is a major challenge. A meta-analysis of randomized trials of adjuvant therapy in early stage breast cancer has indicated that the use of the antiestrogen tamoxifen improves relapse-free and overall survival for postmenopausal women, including those older than age 70 years. Tamoxifen therapy is of greatest benefit in patients whose primary lesions are estrogen- and progesterone-receptor positive, but lesser yet still significant benefits are seen in receptor-negative patients. Adjuvant chemotherapy has only been minimally studied in older women, because earlier trials tended to exclude women older than age 70 years from protocol entry. Trials are needed to explore the role of adjuvant chemotherapy in older women, especially those older than age 70 years. Metastatic breast cancer is incurable. Standard endocrine and chemotherapy regimens may be of great palliative benefit but probably only have modest effects on prolonging survival; older women should be offered such treatment. Initiating treatment for metastases with endocrine therapy does not compromise survival, even when such therapy is given to women who have receptor-negative malignancy. Patients progressing on endocrine therapy or whose metastatic disease is life-threatening should be considered for chemotherapy. Older women in generally good health tolerate standard doses of chemotherapy as well as their younger counterparts. Future research in this setting should include clinical trials designed specifically for the elderly and should include quality-of-life assessment as a major end point.

To perform meta-analysis (MT) on antiemetic efficacy of LAS 30451 (Pancopride) in high and moderately emetogenic chemotherapy (CT).

The response and long-term disease-free survival rates with standard-dose salvage chemotherapy for advanced ovarian cancer are commonly reported to be less than 20 and 10%, respectively. More than 200 women with advanced, refractory, ovarian cancer have received high-dose chemotherapy regimens with autologous bone marrow support (ABMS) for their disease. A feature of the vast majority of the studies is the strikingly high response rates of 70-82% achieved when marrow-supported intensive therapy is administered to women with refractory ovarian cancer. Applying such high-dose therapy earlier in the disease course when the tumors are less resistant will likely produce durable antitumor effects. To further evaluate the effectiveness of high-dose therapy, the Southwest Oncology Group (SWOG) has initiated a phase II study for stage III/IV ovarian cancer with residual disease (microscopic up to 3 cm) following one cisplatin- or carboplatin-based induction regimen (SWOG 9106). Patients will be randomized to receive one of two high-dose regimens with ABMS: cyclophosphamide, cisplatin, and thiotepa or cyclophosphamide, carboplatin, and mitoxantrone. This initial trial is a feasibility study to evaluate whether such high-dose regimens can be given in a cooperative group setting to the ovarian cancer patient population. If the trial is successfully completed, one of the two regimens will be chosen (based on lesser toxicity) to use in a phase III randomized trial of high-dose therapy and ABMS versus standard therapy for high-risk ovarian cancer patients.

A number of prognostic factors have been reported to influence the probability of developing nausea and vomiting after cytotoxic chemotherapy. This study used data collected in four randomized anti-emetic trials conducted by the Clinical Trials Group of the National Cancer Institute of Canada (NCIC-CTG) to assess the consistency of the effects of these prognostic factors. A total of 582 patients, all of whom had received moderately emetogenic chemotherapy for the first time, but who were assigned to different anti-emetics, were included in the analysis. The major findings was that the probability of post-chemotherapy nausea and vomiting was much more strongly influenced by the type of chemotherapy given and the type of anti-emetic used than by patient (e.g., age, gender) or environmental (e.g., treatment location, time of administration) characteristics. Further, patient-related factors had different, and sometimes opposite, effects in different anti-emetic and chemotherapy subgroups. Finally, the relative potency of anti-emetics appeared to vary with chemotherapy regimens. Implications of these findings for future studies are discussed.

A retrospective analysis was made of 1057 young patients (aged 15-29) with Hodgkin's disease (HD) who were entered into British National Lymphoma Investigation (BNLI) trials and studies between 1970 and 1992, and who had attained complete remission and remained disease-free thereafter from either their first-line (n = 774) or second-line (n = 283) treatment. Overall survivals at 20 years for those remaining disease-free from first-line and second-line treatment were 93% and 84%, respectively, compared to a survival of approximately 98.5% in the general population. In young patients cured by modern first-line therapeutic techniques, long-term survival should in future be only a little below that expected in the general population, and the emphasis of future trials should be directed towards the improvement of the efficacy of first-line treatment.

Aging influences the disposition and effects of several classes of drugs. Although drug clearance rate is correlated with toxicity for many anticancer drugs, few data have been published concerning the relationship of aging and clearance of chemotherapy. This study was performed to identify any relationship between age and clearance rate for anticancer drugs in phase I trials at the Johns Hopkins Oncology Center. In a retrospective study, we examined the clinical and pharmacokinetic data for 344 adults (aged 21-77 years) who received 9 phase I drugs with linear clearance in 13 clinical trials. We sought correlations between age and clearance for each drug and for the whole group. Data available for 9 of the 13 trials were used to compare age (< 65 or > 65 years) versus dose delivered [< the maximum tolerated dose (MTD) vs > or = the MTD] or toxicity (< grade 3 vs > or = grade 3). Of 344 patients, 81 (23.5%) were > 65 years old, 34 (9.9%) were > or = 70 years old, and 5 (1.5%) were > or = 75 years old. There was no significant correlation between drug clearance and age for individual drugs or the group as a whole. There was no significant difference between patients of the older and younger age groups with regard to dose or toxicity. Although only a small number of patients aged > or = 75 years were treated, our results suggest that the elderly do not experience greater toxicity even when treated at doses comparable with those given younger patients and should not be excluded from phase I trials on the basis of age. As the population of the United States ages, more elderly patients will be candidates for chemotherapy. A more thorough examination of the relationships between age, clearance rate, and toxicity can be accomplished as active drugs enter phase II/III studies.

The aim of this paper is to compare ondansetron to other antiemetic products used in cancerology. Twenty randomised trials studying ondansetron, and published in international reviews, were analyzed and synthesized. The conclusion is that ondansetron is of demonstrated short term efficiency. It seems to be slightly more efficient than metoclopramide, and its association with dexamethasone increases its efficiency. Doses of 8 mg or 24 mg do not differ from doses of 32 mg, and bolus administration from infusion administration. There are no data on the duration of the protection after the first course of chemotherapy.

Chemotherapy-induced emesis is one of the most common and severe side effects of systemic cancer therapy. During the 1980s, the development of metoclopramide-based combination antiemetic regimens resulted in complete or near-complete control of emesis in 60-70% of patients receiving cisplatin-based chemotherapy. However, 30-40% of patients remained poorly controlled with these regimens, and bothersome side effects such as extrapyramidal symptoms and sedation hindered therapy in some patients. The selective 5-hydroxytryptamine (serotonin) inhibitors are a new class of antiemetics that have further improved the control of chemotherapy-related nausea and vomiting. Ondansetron, the first of these compounds available commercially, has proven superior to high-dose metoclopramide in controlling cisplatin-induced emesis. In addition, no extrapyramidal side effects have been observed with ondansetron. Although the currently approved dosing schedule for ondansetron is 0.15 mg/kg intravenously (IV) every 4 hours for three doses, recent data indicate that a single 32 mg dose prior to chemotherapy may be superior. The addition of dexamethasone (10-20 mg IV prior to chemotherapy) improves the efficiency of ondansetron; this combination should be considered in all patients receiving cisplatin-based chemotherapy. The role of ondansetron in non-cisplatin chemotherapy is not completely defined, but patients unresponsive to other antiemetic therapy often have improved control with the addition of ondansetron.

Doxorubicin and ifosfamide are currently the two main drugs for the treatment of soft tissue sarcomas in adults. Given in combination at full doses, with or without dacarbazine, these agents have induced higher response rates than were obtained with single-agent therapy. Because they involve considerable myelotoxicity, however, full-dose regimens should be reserved for patients with good performance status and without potential septic foci. Obviously, higher response rates do not automatically translate into improved survival. In soft tissue sarcomas, full-dose polychemotherapy will most probably provide a survival benefit only in selected patients in whom surgery can be performed in combination with chemotherapy. Prospective trials in such patients, although difficult to carry out, would be highly desirable. The information they would provide might help the clinician tailor treatment in a more rational way and improve chances of cure or long-term survival in at least some patient subgroups.

To determine if chemotherapy dose intensity influences treatment outcome in advanced ovarian cancer, all randomised studies of first line chemotherapy, published between 1975 and 1989, were analysed for relationships between planned dose intensity and (a) objective response and (b) median survival. Total dose intensity of each study regimen was calculated and a weighted regression model providing for systemic differences in response or survival among studies was utilised. Hence, treatment arms of different studies were never directly compared. In addition, relative dose intensities of individual drugs within combinations was similarly evaluated. The improvement in objective response rate when adding one unit of total dose intensity ranged between 12% and 16% depending on baseline response rate. The improvement in median survival when adding one unit of total dose intensity ranged between 2 and 4 months. One unit of total dose intensity corresponds to, for example, 20 mg m2 week of cisplatin, or 25 mg m2 week of doxorubicin, or 350 mg m2 week of cyclophosphamide. The analysis of individual drugs suggested that doxorubicin and the platinum compounds were about equally effective, with cyclophosphamide being less effective. The methodological benefits and limitations of the approach used and the implication of the results are discussed.

Clinical trials of adjuvant therapies usually measure the effectiveness of treatments by comparing disease-free survival or overall survival. These take into consideration only indirectly the quality of life experienced by the patients. We present some approaches that were developed to assess the impact of adjuvant therapy on the quality of life of breast cancer patients, as well as new methods created to compare treatments based on time spent without symptoms and toxicity (TWiST). The integration of these two methods (measuring quality and comparing duration of time) will provide a new tool for evaluating benefits from treatments given in the adjuvant setting.

Taxol is a new anti-cancer drug that is a natural product derived from the bark of the Pacific Yew tree. The drug promotes polymerization and stabilization of tubulin to microtubules and interferes with the mitotic spindle. Clinical trials indicate that taxol is effective in the treatment of patients with refractory ovarian cancer, breast cancer, malignant melanoma and probably other solid tumors. Toxicities include anaphylactoid reactions, leukopenia, peripheral neuropathy and oropharyngeal mucositis. Increased supplies of the drug are required to support further phase II and III testing.

To determine whether the dose intensity of chemotherapeutic regimens correlates with the complete remission rate in adult patients with advanced-stage intermediate-grade lymphoma, reports of comparative trials of therapy were reviewed. Reports were identified using MEDLINE, through references from review articles, and through review of selected abstracts. Twenty-two studies including 14 randomized and eight cohort trials were analyzed to assess projected dose intensity. Four other studies were analyzed to assess the role of received dose intensity. Dose intensities were calculated using described methods and correlated with complete remission rates. Individual trials were assessed using "levels of evidence." A metaanalysis of randomized trials and a cross-trial analysis of all comparative trials using a weighted least squares linear regression were performed. Using levels of evidence, support was obtained for the hypothesis that dose intensity correlates with the remission rate from two trials in which dose intensity was "indirectly" tested. As these studies did not "directly" test dose intensity, confounding variables, including those arising from the assumptions made in calculating dose intensity, cannot be excluded. Metaanalysis showed a relative probability of achieving complete remission of 1.34 (95% confidence interval, 1.13 to 1.58) favoring the pooled arm of high dose intensity. Cross-trial analysis showed a relatively weak association between dose intensity and remission rate (r = .49, P = .0001). Two of four reports retrospectively assessing received dose intensity suggested that increased dose intensity is associated with superior remission rates. These analyses suggest that dose intensity may correlate with the remission rate in advanced-stage intermediate-grade lymphoma. However, properly designed trials directly testing dose intensity have not been performed and are needed to confirm this hypothesis.