Principal Toxicity Research Articles

Phase 2 trial of carboplatin, paclitaxel, and irinotecan in ovarian, fallopian tube, and primary peritoneal cancers

Objective. Our goal in this nonrandomized phase 2 trial was to evaluate the toxicity and obtain preliminary data on the potential efficacy of a novel three-drug combination regimen (carboplatin–paclitaxel–irinotecan) when employed as initial therapy of advanced ovarian cancer or as second-line treatment in the setting of a prolonged (≥12 months) treatment-free interval. Methods. Patients with a histologically confirmed diagnosis of advanced ovarian cancer, primary adenocarcinoma of the peritoneum, or fallopian tube cancer were enrolled in the study. Patients received carboplatin (AUC 5), paclitaxel (150 mg/m 2 over 3 h), and irinotecan (100 mg/m 2 over 90 min). The three-drug combination was initially administered on an every 21-day schedule, but due to toxicity was subsequently changed to a 28-day program. Results. A total of 30 patients were enrolled into this phase 2 trial. Twenty-three patients were chemotherapy naive, while 7 had received prior chemotherapy. Seventeen patients completed all six cycles of treatment. Eight patients (27%) were removed from the study after a median of three cycles due to toxicities. Seventeen patients (57%) experienced grade 4 neutropenia, with three individuals requiring hospitalization for neutropenic fever and dehydration. Grades 3 and 4 thrombocytopenia were experienced by three patients each. The principal nonhematologic toxicities were diarrhea (grade 3: three patients) and fatigue. The overall objective clinical response rate was 83%. Conclusions. The combination of carboplatin–paclitaxel–irinotecan can be administered to women with advanced ovarian cancer with significant, but overall acceptable toxicity. Modification of the regimen from a 3-week to a 4-week schedule permits a greater percentage of patients to complete the program without experiencing excessive toxicity. The overall objective response rate observed in this trial is comparable to other combination regimens employed in this setting. Defining a place for this three-drug program in the standard management of ovarian cancer will require the conduct of an appropriately designed randomized trial.

Fatal drug poisonings: medico-legal reports and mortality statistics

The entire fatal drug poisoning panorama in Finland is considered in terms of three categories: accidental, self-inflicted and undetermined (whether accidental or with intent to harm) deaths. The study material consisted of all 500 deaths in 1997 that medical examiners, after examination(s) at the Forensic Toxicology Division (FTD) of the Department of Forensic Medicine, University of Helsinki, officially certified as resulting from drug poisoning. These deaths were matched with data on the same deaths registered at Statistics Finland (SF), the national mortality statistics office. The SF register included 72 additional instances of deaths resulting from drug poisoning. In all but two of these cases, the cause-of-death determination was based on a medico-legal inquest with autopsy and forensic toxicological examination(s) and was certified, in most of the cases, as due to the alcohol component in multiple-toxicant combinations. Reclassifying these deaths at SF to the category of drug component is in accordance with current International Classification of Diseases (ICD-10) regulation of coding “to the medicinal agent when combined with alcohol”; the principle and practice, which is recommended to be amended to equalize the status of alcohol and drug when explicitly stated by a forensic examiner as the principal toxicant in combined poisonings. With regard to manner-of-death, the agreement rates between medico-legally proven deaths from drug poisoning and those registered at SF were 79.8% for accidents, 98.5% for suicides and 0% (nil) for undetermined deaths, at the level of three-character external cause codes (E-code). All deaths originally certified as undetermined were re-assigned, most frequently to the category of accidental death. Since within an advanced and sophisticated medico-legal system, a medical examiner’s evidence-based statement, even when the conclusion reached is undetermined (as to intent), should be taken as a compelling argument, the practice of reclassification cannot be considered advisable because assembled information is lost. Concerning the assigned drug-specific groups, the agreement according to the manner-of-death between certifications and registrations was fairly good. From among the accidents, however, opioid poisonings were re-assigned in 11 (29.7%) cases, mostly to the drug abuse/dependence categories, i.e. they were considered as natural deaths by the statistics office. The drug-specific observations were possible only by using the codes from the Anatomical Therapeutic Chemical (ATC) classification of drugs. This is why the incorporation of ATC codes into the ICD system, whenever reasonable, is recommended.

The alkylating agent penclomedine induces degeneration of purkinje cells in the rat cerebellum.

Penclomedine (PEN), a multichlorinated alpha-picoline derivative which is metabolized to highly reactive alkylating species, was selected for clinical development due to its prominent activity against a wide range of human tumor xenografts when administered either parentally or orally. Its principal dose-limiting toxicity in preclinical and clinical studies has been neurocerebellar toxicity, which has been related to the magnitude of peak plasma PEN concentrations, but not to plasma concentrations of its putative principal alkylating metabolite, 4,o-demethylpenclomedine (DMPEN). These observation, as well as PEN's toxicologic, pharmacologic, and tissue distribution profiles, have suggested that the parent compound is primarily responsible for cerebellar toxicity. The studies described in this report were undertaken to characterize the neuropathology of PEN neurotoxicity, with a long-term goal of developing strategies to maximize its therapeutic index. Male Sprague-Dawley rats were treated with therapeutically relevant doses of PEN, orally and intraperitoneally (i.p.), on various administration schedules, and DMPEN administered i.p. The animals were monitored for neurotoxicity, and brain sections were examined for neuropathology, particularly Purkinje cell loss and neuronal injury. Brain sections were stained using standard histochemical techniques and immunostained with OX-42 to detect microglial cells that are activated following neuronal damage, and calbindin D(28K), a calcium-binding protein expressed by cerebellar Purkinje cells. Dose-related neurocerebellar toxicity associated with parasagittal bands of Purkinje cell degeneration and microglial activation in the cerebellar vermis were evident in rats treated with PEN 100-400 mg/kg i.p. as a single dose. Neuronal injury was not observed in other regions of the brain. Furthermore, neither clinical nor histopathological evidence of cerebellar toxicity was apparent in rats treated with similar total doses of PEN administered i.p. on a dailyx5-day dosing schedule. Similar histological findings, in an identical neuroanatomical distribution, were observed in rats treated with PEN orally; however, the magnitude of the neuronal toxicity was much less than in animals treated with equivalent doses of PEN administered i.p. Although acute lethality occurred in some rats treated with equimolar doses of DMPEN as a single i.p. treatment, surviving animals exhibited neither signs nor histopathological evidence of neurocerebellar toxicity. PEN produces selective dose- and schedule-dependent Purkinje cell degeneration in the cerebellar vermis of rats, whereas therapeutically relevant doses of PEN administered orally are better tolerated and produce less neurocerebellar toxicity. In addition, roughly equivalent, albeit intolerable, doses of the major active metabolite DMPEN, which was lethal to some animals, produced neither clinical manifestations of neurocerebellar toxicity nor Purkinje cell loss. These results support a rationale for investigating whether PEN administered orally, which may undergo significant first-pass metabolism to DMPEN and other less toxic intermediates, or treatment with DMPEN, itself, may result in less neurocerebellar toxicity and superior therapeutic indices than PEN administered parenterally.

Salvage chemotherapy according to the ASHAP protocol: a single-center study of 24 patients with relapsed or refractory aggressive non-Hodgkin's lymphomas.

Numerous salvage protocols for relapsed or refractory aggressive non-Hodgkin's lymphomas have been described. The purpose of this retrospective study was to evaluate the efficacy and the toxicity of the ASHAP protocol, which combines a continuous infusion of doxorubicin and cisplatin with high-dose cytarabine and methylprednisolone. Twenty-four patients with relapsed or refractory aggressive non-Hodgkin's lymphomas were treated with a median of 3 cycles (range: 1-5) of ASHAP. Twelve patients achieved a complete and four a partial remission for an overall response rate of 67%. The 3-year overall and progression-free survival rates were 60% and 40%, respectively. Ten of the responding patients were consolidated by high-dose chemotherapy. After a median follow-up of 15.5 months, four patients are in continuous complete remission, while six patients suffered relapses (two fatal). For reasons of low risk profile [international prognostic index (IPI) score of 0, n=2] or age >60 years ( n=4), consolidation was limited to involved-field radiotherapy in six patients. All of these patients are alive after a median follow-up of 37 months, with two relapses. Factors predicting a poor response to salvage therapy were primary refractory disease, elevated lactate dehydrogenase activity, and an IPI score of >/=2. The principal toxicity was myelosuppression with grade III or IV neutropenia or thrombocytopenia occurring in 88% or 75%, respectively, of the patients. Nonhematological toxicity was generally mild. There were no treatment-related deaths. The ASHAP regimen is a highly active and well-tolerated salvage protocol for patients with relapsed aggressive non-Hodgkin's lymphomas which compares favorably with other established protocols.

Fludarabine in Waldenstrom's macroglobulinemia

Waldenstrom's macroglobulinemia (WM), a rare B-cell malignancy, is incurable. Conventional treatment consists of alkylating agents (especially chlorambucil), with or without corticosteroids. Purine analogues such as fludarabine are also active. Response rates to first-line therapy range from 38% to 85%. Discrepancies in response rates between different studies could be due to the small patient populations in two studies and to differences in patient characteristics and response criteria. Since 1990, several phase 2 trials of purine analogues have been done with previously treated patients; fludarabine induced responses in about one third of patients who were resistant to previous treatments. Response rates to fludarabine in previously treated patients range from 30% to 50% and are highest among patients who are still sensitive to their primary therapy. The responses last from 32 to 41 months. The principal toxicity of fludarabine is myelosuppression. Trials of fludarabine combination therapy with drugs such as rituximab are ongoing. Semin Oncol 30:239-242. © 2003 Elsevier Inc. All rights reserved.

Phase II trial of paclitaxel, ifosfamide, and carboplatin in extensive-stage small cell lung cancer

Extensive-stage small cell lung cancer (ES-SCLC) remains a therapeutic challenge to the medical oncologists. We evaluated the triplet combination of paclitaxel (175 mg/m 2 over 1 h), ifosfamide (2.5 gm/m 2 over 1 h) and carboplatin (AUC=6 over 0.5 h) (PIC) all given on day 1 of a 21 day schedule. Thirty-five patients were entered with a median age of 59 years (range 40–79). The ECOG PS was 0–1 in 86%. A median of 6 cycles were delivered (range 1–6). The principal toxicity was neutropenia with 66% of patients experiencing grade 4 neutropenia. Only 9% of patients experienced febrile neutropenia. One treatment-related death (3%) due to neutropenic sepsis occurred. Non-hematologic toxicity was minimal. The overall response rate was 71% (15% complete response, 56% partial responses). Quality of life appeared to be stable across time. The median survival time was 9.5 months (95% confidence interval (CI), 6.7–13.2 months) with a 1- and 2-year survival rates of 43% (95% CI, 26–59%) and 16% (95% CI, 2–30%). PIC has activity in ES-SCLC and is associated with a response rate and survival profile similar to other combinations in this disease setting. This regimen has a tolerable toxicity profile and a favorable and convenient administration schedule.

Advancing role of radiolabeled antibodies in the therapy of cancer.

This review focuses on the use of radiolabeled antibodies in the therapy of cancer, termed radioimmunotherapy (RAIT). Basic problems concerned with the choice of antibody, radionuclide, and physiology of the tumor and host are discussed, followed by a review of the pertinent clinical publications of various radioantibody constructs in the treatment of hematopoietic and solid tumors of diverse histopathology, grade, and stage, and in different clinical settings. Factors such as dose rate delivered, tumor size, and radiosensitivity play a major role in determining therapeutic response, while target-to-nontarget ratios and, particularly, circulating radioactivity to the bone marrow determine the principal dose-limiting toxicities. RAIT appears to be gaining a place in the therapy of hematopoietic neoplasms, such as non-Hodgkin's lymphoma: several agents are advancing in clinical trials toward registration, and one has recently been approved by the FDA. Although RAIT of solid tumors has shown less progress, use of pretargeting strategies, such as an affinity-enhancement system consisting of bispecific antibodies separating targeting from delivery of the radiotherapeutic, appears to enhance tumor-to-nontumor ratios, and may increase radiation doses to tumors more selectively than directly labeled antibodies.

ALIMTA® (pemetrexed disodium) as second-line treatment ofnon-small-cell lung cancer: a phase II study

The purpose of this study was to evaluate ALIMTA (pemetrexed disodium, LY231514), a multi-targeted antifolate with first-line activity against non-small-cell lung cancer (NSCLC), in a second-line setting. Patients with NSCLC were eligible for this phase II study if they had progressive disease within 3 months after first-line chemotherapy or progression while being treated with first-line chemotherapy. In 81 patients studied, two cohorts of patients were assigned based on whether the first-line therapy had included a platinum regimen. ALIMTA was administered at 500 mg/m2 by 10-min intravenous infusion once every 21 days. The response rate in the 79 evaluable patients with poor prognostic features was 8.9% [95% confidence interval (CI) 2.6% to 15.1%]. The response rate in the platinum-pretreated group was 4.5% and 14.1% in the non-platinum-pretreated group. The median duration of response was 6.8 months (95% CI 3.4-7.8 months, 0% censoring). The median survival time was 5.7 months (95% CI 4.0-8.3 months, 7.6% censoring). The probability of survival for at least 6 months was estimated to be 48%. The median time to disease progression was 2 months (95% CI 1.4-2.8 months, 0% censoring). The principal toxicity was myelosuppression, which was reversible. ALIMTA is active in a second-line setting in non-platinum-pretreated NSCLC patients progressing within 3 months of first-line chemotherapy. This study demonstrates that it is possible to evaluate new drugs against NSCLC in a second-line setting.

Concurrent two-dimensional radiotherapy and weekly docetaxel in the treatment of stage III non-small cell lung cancer: a good local response but no good survival due to radiation pneumonitis

Docetaxel is a novel, potentially highly beneficial drug for the treatment of lung cancer, and has shown remarkable radio-sensitizing effects in vitro. In the present study, we evaluated whether weekly docetaxel (20 mg/m 2) and conventionally fractionated radiotherapy with the two-dimensional (2D) technique could be tolerated and effective in the treatment of locally advanced non-small-cell lung cancer (NSCLC). Thirty-two stage III (IIIA:13, IIIB:19) NSCLC patients were treated with weekly administration of docetaxel (20 mg/m 2) on days 1, 8, 15, 22, 29 and 36 in addition to concurrent radiation therapy. The total tumor dose was 60–66 Gy given with a 2D technique in 6–7 weeks. Complete response was observed in 9/32 (28%) patients and partial response in 20/32 (63%). Three (9%) patients died of chemoradiation-induced pneumonitis after completion of therapy. In total, grade >3 toxicities included pneumonitis (47%) and esophagitis (16%). The median overall survival duration was 12 months. The dimensions of the radiotherapy port were larger in patients who produced severe (grade >3) chemoradiation pneumonitis than in patients who did not ( P<0.05). The median survival time was 12.4 months and 2-year overall survival were 35%. The survival was better in patients whose first radiotherapy port dimensions were less than 150 cm 2 compared to patients whose first radiation port dimensions were ≧150 cm 2 ( P<0.05). In conclusion, concurrent weekly administration of docetaxel (20 mg/m 2) with 2D radiotherapy for NSCLC, had good local response, but survival rate was not completely satisfactory due to chemoradiation pneumonitis, which was the principal toxicity that adversely affected prognosis in elderly patients whose radiotherapy port was large.

Irinotecan in non-small-cell lung cancer: status of ongoing trials.

Irinotecan possesses significant single-agent activity in non-small-cell lung cancer (NSCLC) and is active in combination with either cisplatin or carboplatin. Two phase III trials completed in Japan have suggested that the combination of irinotecan/cisplatin yields superior survival rates in stage IV NSCLC patients compared to vindesine/cisplatin. The principal toxicities of the irinotecan/cisplatin regimen are neutropenia and diarrhea. This regimen is currently being tested in Japan against regimens commonly used in the United States, such as cisplatin/gemcitabine, cisplatin/vinorelbine, and carboplatin/paclitaxel. These studies include evaluation of monthly as well as weekly schedules of cisplatin in combination with irinotecan as well as a triplet regimen of irinotecan/carboplatin/paclitaxel. Ongoing trials are evaluating these regimens as well as irinotecan/carboplatin and several nonplatinum-based irinotecan-containing doublets in both the first- and second-line treatment of advanced NSCLC. Several ongoing trials are attempting to integrate irinotecan with thoracic radiation therapy in stage III NSCLC. These trials are using irinotecan-containing regimens as induction and concurrent therapy with thoracic radiation therapy. Irinotecan is also being evaluated in the preoperative setting in early-stage resectable NSCLC. Many of these trials are also incorporating celecoxib, a potent inhibitor of the cyclooxygenase-2 pathway, in combination with irinotecan-containing regimens in both advanced as well as early-stage NSCLC. Future trials should focus on the integration of the new targeted agents in combination with irinotecan-containing regimens in all stages of NSCLC.

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0–2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m 2), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47–75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4–59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m 2 of gemcitabine and 100 mg/m 2 of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.

Multivariate biological profiling and principal toxicity regions of compounds: the PCB case study

AbstractThe chemometric QSAR strategy, as applied in environmental sciences and drug design, is based on (1) multivariate characterization of chemical structure, (2) multivariate design in the principal properties of a set of compounds to select a representative training set, and (3) multivariate modelling of the structure–activity relationships. A multivariate QSAR investigation is often commenced by applying a screening design, and the selected compounds are tested biologically in a broad battery of test systems (‘multivariate biological profiling’). In many cases the result is such that for certain biological end‐points only some of the tested compounds are active, while for another set of biological end‐points other tested chemicals are active. In other words, when looking at the chemical property space, there may be both responding and non‐responding toxicity regions, or even regions of very specific toxicity mechanisms. This may lead to loss of resolution and balance in the resulting QSAR models. Therefore it might sometimes be worthwhile to focus the QSAR modelling on parts of the chemical space where high toxicity is expected or known to be the case. In this paper we describe a multi‐stage modification of the chemometric QSAR strategy, aimed at identifying focused sets of compounds that provide a good mapping of such principal toxicity regions. This strategy is based on PCA, PLS and multivariate design in several stages. The strategy is illustrated using a data set of polychlorinated biphenyls, a set of compounds for which seven biological end‐points were determined. Copyright © 2002 John Wiley &amp; Sons, Ltd.

Phase II trial of pemetrexed disodium (ALIMTA®, LY231514) in chemotherapy-naïve patients with advanced non-small-cell lung cancer

BackgroundTo evaluate the efficacy and safety of pemetrexed therapy for chemotherapy-naïve patients with surgically incurable non-small-cell lung cancer (NSCLC). Patients and methodsEligible patients received pemetrexed 600 mg/m2 every 3 weeks. Restaging was performed after every two cycles of therapy and toxicity was assessed at each cycle of pemetrexed. In the absence of disease progression or undue toxicity, treatment was continued for a maximum of 12 cycles. ResultsFifty-nine patients (median age 59 years; range 39–74 years) received a median of four cycles of pemetrexed. Nineteen patients (32%) had a ECOG performance status (PS) of two and 39 patients (66%) had stage IV disease. The most common histological sub-types were adenocarcinoma (20 patients, 34%) and large cell (18 patients, 31%). Sixteen patients (27%) had received prior radiotherapy. Nine patients achieved a partial response for an overall response rate of 15.8% (95% confidence interval CI 7% to 28%). The median duration of response was 4.9 months, and the median survival was 7.2 months. The principal toxicities were myelosuppression and rash. While grade 3 or 4 neutropenia was seen in 25 patients (42%), only two patients (3%) developed grade 3 infection. Eighteen patients (31%) developed grade 3 or 4 cutaneous toxicity, which improved with prophylactic oral dexamethasone administered for 3 days beginning the day before pemetrexed treatment. Asymptomatic elevations in hepatic biochemistry (especially alanine transaminase and aspartate transaminase) were seen in47 patients (80%); however, these did not interfere with the dose or schedule of pemetrexed and returned to normal levels throughout the study. ConclusionsThis is the largest study confirming the encouraging single-agent activity of pemetrexed in chemotherapy-naïve patients with NSCLC. In addition, this study demonstrates that a dose of 600 mg/m2 can be delivered safely; however, treatment should be restricted to patients with a PS of 0 or 1. The results of combination studies are awaited with interest.

Capecitabine (Xeloda®) in combination with oxaliplatin: a phase I, dose-escalation study in patients with advanced or metastatic solid tumors

ObjectivesThis phase I, dose-escalation study was conducted to determine the recommended dose of intermittent oral capecitabine in combination with a fixed dose of i.v. oxaliplatin. Secondary objectives included evaluation of the safety profile and antitumor activity. Patients and methodsTwenty-three patients with advanced or metastatic solid tumors received a 21-day regimen of oral capecitabine (500, 825, 1000 or 1250 mg/m2 twice daily, days 1–14) in com-bination with oxaliplatin (130 mg/m2, 2-h i.v. infusion, day 1). Dose-limiting toxicities were determined during the first treatment cycle, and safety and efficacy were evaluated throughout treatment. ResultsThe recommended dosing schedule is oral capecitabine 1000 mg/m2 twice daily (days 1–14) with i.v. oxaliplatin 130 mg/m2 (day 1) in a 21-day treatment cycle. The principal dose-limiting toxicity was diarrhea. The most frequent treatment-related adverse events occurring during the study were gastrointestinal (nausea/vomiting, diarrhea) and neurological (dysesthesia, paresthesia). The majority of treatment-related adverse events were mild to moderate in intensity, and no grade 4 adverse events occurred in the 15 patients treated at or below the recommended dose. The most common grade 3/4 laboratory abnormalities were lymphocytopenia (52% of patients), thrombocytopenia (22%; grade 3 only), neutropenia (17%) and hyperbilirubinemia (17%). Among patients treated at or below the recommended dose level (n = 15), only two patients experienced grade 3 neutropenia and no patients experienced grade 4 neutropenia. Partial tumor responses occurred in six patients (26%), including five of nine patients (55%) with colorectal cancer. All responding patients were pretreated with 5-fluorouracil and four responders had received prior irinotecan. ConclusionsOral capecitabine with i.v. oxaliplatin is a feasible combination regimen that shows promising antitumor activity in patients with colorectal cancer. There is an ongoing, phase II study to further characterize the safety and efficacy of this combination as first-line therapy for metastatic colorectal cancer, using the recommended dose identified in this study.

Phase I, dose-finding study of capecitabine in combination with docetaxel and epirubicin as first-line chemotherapy for advanced breast cancer

PurposeCapecitabine is an oral fluoropyrimidine with considerable activity and minimal myelosuppression and alopecia. This phase I study evaluated the addition of capecitabine to epirubicin/docetaxel combination therapy as first-line treatment for advanced breast cancer. Patients and methodsTwenty-three female patients with advanced breast cancer received capecitabine (765–1060 mg/m2 twice daily on days 1–14 of a 3-week treatment cycle) in combination with epirubicin and docetaxel (75 mg/m2 i.v. on day 1). ResultsThe maximum tolerated dose of capecitabine was 985 mg/m2 and the principal dose-limiting toxicity was febrile neutropenia. No grade 3/4 anemia or thrombocytopenia occurred. There were no grade 4 non-hematological events and grade 3 events other than alopecia were rare. Alopecia occurred in all patients and treatment cycles, and asthenia occurred in all patients and in 84% of treatment cycles. Other frequent adverse events included nausea, vomiting, fever, paresthesia and elevated transaminase levels. An objective response to treatment was observed in 91% (95% confidence interval 72% to 99%) of patients. ConclusionsThe addition of capecitabine to docetaxel/epirubicin combination therapy provides a well-tolerated and active first-line chemotherapy regimen in patients with advanced breast cancer, and merits phase II/III evaluation.

A phase III randomized trial comparing vindesine and cisplatin with or without ifosfamide in patients with advanced non-small-cell lung cancer: long-term follow-up results and analysis of prognostic factors

In order to evaluate the activity and toxicity of a three-drug combination of vindesine, ifosfamide and cisplatin (VIP) for inoperable non-small-cell lung cancer (NSCLC), we conducted a randomized trial comparing VIP with a two-drug combination of cisplatin and vindesine (VP). Between September 1987 and March 1992, a total of 132 patients with stage III or IV NSCLC were randomly allocated to either VIP or VP. The VIP regimen consisted of vindesine (VDS 3 mg/m 2 on days 1 and 8), ifosfamide (IFX 1300 mg/m 2 on days 1–5), and cisplatin (CDDP 20 mg/m 2 on days 1–5). The VP regimen consisted of VDS and CDDP with the same dose and schedule as the VIP regimen. Both regimens were repeated every 4 weeks. Objective response rates were 49.3% (95% confidence interval: 95%CI, 43.1–55.4%) in the VIP arm and 44.6% (95%CI, 38.4–50.2%) in the VP arm; the difference was not significant ( P=0.5390). Median response duration, median survival time, and two-year survival rates were 26.5 weeks, 49.6 weeks, and 14.9% in the VIP arm and 28.7 weeks, 37.1 weeks, and 12.3% in the VP arm, respectively. There were also no significant differences between these two treatment arms. In comparison with the VP regimen, however, a survival advantage of the VIP regimen could be confirmed when the data were evaluated with Cox's multivariate analysis ( P=0.0131). In both arms, the principal toxicity was myelosuppression, which was significantly more frequent in the VIP arm, although generally well tolerated. Conclusion: This study suggested the survival advantage of the VIP regimen over the VP regimen for treatment of patients with advanced NSCLC.

Oxaliplatin plus vinorelbine in advanced non-small-cell lung cancer: final results of a multicenter phase II study

BackgroundOxaliplatin and vinorelbine are both active agents against non-small-cell lung cancer (NSCLC). In a previous phase I trial, we showed that oxaliplatin (130 mg/m2, day 1) and vinorelbine (26 mg/m2/day, days 1 and 8) can be safely combined when given every 21 days. We completed the evaluation of this new platinum-based doublet in advanced NSCLC patients in a multicenter phase II study. Patients and methodsTwenty-eight chemotherapy-naïve patients (22 men and six women; median age 58 years, range 33–70), including 20 with stage IV disease, received this out-patient combination, with 5-hydroxytryptamine-3-receptor agonists as the only prophylactic measure. ResultsA total of 117 cycles were given, for a median of three per patient (range 1–8). Of 26 eligible patients, nine achieved a partial response (WHO criteria), giving an objective response rate of 35% [95% confidence interval (CI) 17% to 56%]. The median progression free survival was 5.0 months (95% CI 3.1 to 6.9), median overall survival was 9.8 months (95% CI 2.2 to 17.5) and the 1-year survival rate was 37%. Neutropenia was the principal toxicity, grade 4 occurring in 11 patients (39%) and 25cycles (22%). Four patients (14%) experienced one episode of febrile neutropenia each. Acute oxaliplatin-related neurosensory toxicity was prevalent, but was mild to moderate in the majority of patients (82%) and reversible. Grade 1/2 vomiting (65% of patients) and diarrhea (32% of patients) were easily managed. ConclusionsThe oxaliplatin–vinorelbine doublet is a safe and active out-patient combination. It may represent an interesting alternative in the management of patients with NSCLC, and serve as a new doublet to which other active agents could be added.

A randomised trial of oral versus intravenous topotecan in patients with relapsed epithelial ovarian cancer

A multicentre, randomised study was carried out in Europe, South Africa and North America to compare the activity and tolerability of oral versus intravenous (i.v.) topotecan in patients with relapsed epithelial ovarian cancer. Patients who had failed first-line therapy after one platinum-based regimen, which could have included a taxane, were randomised to treatment with either oral (p.o.) topotecan, 2.3 mg/m2/day or i.v. topotecan 1.5 mg/m2/day for 5 days every 21 days. Patients were stratified by prior paclitaxel exposure, interval from previous platinum therapy and tumour diameter. 266 patients were randomised. Response rates were 13% orally (p.o.) and 20% (i.v.) with a complete response in 2 and 4 patients, respectively. The difference in the response rates was not statistically significant. Median survival was 51 weeks (p.o.) and 58 weeks (i.v.) with a risk ratio of death (p.o. to i.v. treatment) of 1.361 (95% confidence interval (CI): 1.001, 1.850). Median time to progression was 13 weeks (p.o.) and 17 weeks (i.v.). The principal toxicity was myelosuppression although grade 3/4 neutropenia occurred less frequently in those receiving oral topotecan. Toxicity was non-cumulative and infectious complications were relatively infrequent. Non-haematological toxicity was generally mild or moderate. The incidence of grade 3/4 gastrointestinal events was slightly higher for oral than i.v. topotecan. Oral topotecan shows activity in second-line ovarian cancer and neutropenia may be less frequent than with the i.v. formulation. A small, but statistically significant, difference in survival favoured the i.v. formulation, but the clinical significance of this needs to be interpreted in the context of second-line palliative treatment. Oral topotecan is convenient and well tolerated and further studies to clarify its role are ongoing.

A phase II study of gemcitabine plus cisplatin in patients with advanced non-small cell lung cancer: clinical outcomes and quality of life

The aim of the present phase II study was to assess the activity and safety of gemcitabine–cisplatin combination in advanced NSCLC, and to evaluate the impact of this regimen in terms of symptom benefit and quality of life (QOL). Eighty patients with pathologically confirmed advanced (stage IIIB and IV) NSCLC were enrolled into this study. Gemcitabine was administered on days 1, 8 and 15 at a dose of 1000 mg/m 2, and cisplatin was given on day 2 at a dose of 100 mg/m 2. The cycles were repeated every 4 weeks. The impact of treatment on QOL and on tumor-related symptoms was evaluated with the validated EORTC forms (QLQ-C30 and LC-13). The regimen was relatively well tolerated. Myelosuppresion was the principal toxicity. Grade 3/4 neutropenia, thrombocytopenia and anemia occurred in 58, 65 and 30% of patients respectively. In 143 cycles (35%) the administration of gemcitabine on day 15 was omitted due to myelosuppresion. Non-hematological toxicities were generally mild. Among the 76 patients available for response evaluation, there were 5 complete responses (7%) and 26 partial responses (34%); an overall response rate of 41%. The median duration of response was 8.0 months. The median survival for all 80 patients was 11.0 months and the actuarial 1-year survival probability 45%. During therapy global QOL improved in 22% of patients and particular functional domains increased in 19–37% of patients. Dyspnea was released in 36% of patients, fatigue in 45%, chest pain in 38%, shoulder pain in 27%, cough in 44%, and hemoptysis in 75%. The mean intensity scores of the last three symptoms decreased significantly with therapy. Our study confirmed relatively high efficacy of the gemcitabine–cisplatin combination in patients with advanced NSCLC. Of particular importance was that treatment with gemcitabine–cisplatin combination in a large proportion of patients was also associated with remarkable symptomatic release and with improvement of QOL. However, the high frequency of myelotoxicity-related gemcitabine omissions on day 15 of the cycle indicates that modification of the schedule should be considered in standard care.

A phase I study of sequential intravenous topotecan and etoposide in lung cancer patients

The topoisomerase I inhibitor topotecan (T) and the topoisomerase II inhibitor etoposide (E) are active drugs in lung cancer. The complementary functions of their targets may suggest benefit from the combined use of these agents but drug scheduling has been shown to play a critical role in preclinical models. To establish the optimal schedule and assess the impact of sequential administration of the combination of T and E, we conducted a dose finding study of sequential intravenous T and E in a four-weekly-schedule in relapsed lung cancer patients. The importance of drug sequence was assessed in consecutive patients throughout all dose levels; patients received in the first course either T followed by E (the TE group: T on days 1-3 and E on days 4-6) or E before T (the ET group: F on days 1-3 and Ton days 4-6). The sequence of Tand E was alternated in the successive courses. In this crossover design, each patient served as his own control for analysis of hematological toxicity in which TE sequence was compared to that of the ET sequence. Moreover, hematological toxicity after the first course was compared between the TE and the ET groups. The starting dose was T/E 0.75/75 mg/m2 at dose level 1and dose escalation was planned to T/E 1.00/75 mg/nm2 at dose level 2, T/E 1.00/100 mg/m2 at dose level 3, T/E 1.25/100 mg/m2 at dose level 4 and T/E 1.50/100 mg/m2 at dose level 5. Nineteen patients (small-cell lung cancer 7, non-small-cell lung cancer 11, mesothelioma 1 patient) were included. The principal toxicity was myelosuppression, primarily neutropenia and thrombocytopenia. At dose level 3 several grade 4 toxicities were observed. DLT (febrile neutropenia) occurred in two patients, one in the TE and one in the ET group and precluded further dose escalation. There was no significant difference in WBC and platelet nadirs during the first course between the TE and the ET group. The influence of the sequence of administration of topotecan and etoposide was calculated by comparing the nadir values of cycles I and II for each patient. For none of the dose levels, a significant sequence-dependent effect could be detected. The MTD was reached at the doses of 100 mg/m2 topotecan and 75 mg/m2 etoposide. No objective responses were seen. Although the combined use of topoisomerase I and II inhibitors is attractive on theoretical grounds, excessive myelosuppression prevents substantial dose escalation.