Phase I and pharmacokinetic study of oral irinotecan given once daily for 5 days every 3 weeks in combination with capecitabine in patients with solid tumors.

PURPOSE: To assess the maximum tolerated dose, dose-limiting toxicity, pharmacokinetics, and preliminary antitumor activity of oral irinotecan given in combination with capecitabine to patients with advanced, refractory solid tumors. PATIENTS AND METHODS: Patients were treated from day 1 with irinotecan capsules given once daily for 5 consecutive days (50 to 60 mg/m2/d) concomitantly with capecitabine given twice daily for 14 consecutive days (800 to 1,000 mg/m2); cycles were repeated every 21 days. RESULTS: Twenty-eight patients were enrolled and received 155 cycles of therapy (median, five cycles; range, one to 18 cycles). With irinotecan 60 mg/m2/d and capecitabine 2 x 800 mg/m2/d, grade 3 delayed diarrhea in combination with grade 2 nausea (despite maximal antiemetic support) and grade 3 anorexia and colitis, were the first-cycle dose-limiting toxicities in two of six patients, respectively. At the recommended doses (irinotecan 50 mg/m2/d; capecitabine 2 x 1,000 mg/m2/d), side effects were mostly mild to moderate and uniformly reversible. Pharmacokinetic analysis showed that there was no interaction between oral irinotecan and capecitabine, and that body-surface area was not significantly contributing to the observed pharmacokinetic variability. Confirmed partial responses were observed in two patients with gallbladder carcinoma and in one patient with melanoma. Disease stabilization was noted in 16 patients. CONCLUSION: The recommended phase II doses for oral irinotecan and capecitabine are 50 mg/m2/d for 5 consecutive days, and 2 x 1,000 mg/m2/d for 14 consecutive days repeated every 3 weeks, respectively.

Seven year update of an EORTC phase III trial of high-dose intensity M-VAC chemotherapy and G-CSF versus classic M-VAC in advanced urothelial tract tumours.

EORTC protocol 30924 is an international randomized trial reporting a 7.3 year update of a 2 weekly regimen of high-dose intensity chemotherapy with M-VAC plus granulocyte colony stimulating factor (HD-M-VAC) compared to classic M-VAC in advanced transitional cell carcinoma (TCC). Two hundred and sixty three untreated patients with bidimensionally measurable TCC were included. In an intention to treat analysis, there were 28 complete responses (CR) (21%) and 55 partial responses (PR) (41%), for an overall response rate (RR) of 64% on the HD-M-VAC arm. On M-VAC, there were 12 CR (9%) and 53 PR (41%), for an overall RR of 50% . The P-value for the difference in CR was 0.009; and for RR, was 0.06. After a median follow-up of 7.3 years, 24.6% are alive on the HD-M-VAC arm vs. 13.2% on the M-VAC arm. Median progression-free survival was better with HD-MVAC (9.5 months) vs. M-VAC (8.1 months). The mortality hazard ratio (HR) was 0.76. The 2-year survival rate for HD-M-VAC was 36.7% vs. 26.2% for M-VAC. At 5 years, the survival rate was 21.8% in the HD-M-VAC vs. 13.5%. Median survival was 15.1 months on HD-MVAC and 14.9 months on M-VAC. There was one death from toxicity in each arm; and more patients died to malignant disease in the M-VAC arm (76%) than in the HD-M-VAC arm (64.9%). With longer follow-up initial results have been confirmed, and shows that HD-M-VAC produces a borderline statistically significant relative reduction in the risk of progression and death compared to M-VAC.

New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.

Anticancer cytotoxic agents go through a process by which their antitumor activity-on the basis of the amount of tumor shrinkage they could generate-has been investigated. In the late 1970s, the International Union Against Cancer and the World Health Organization introduced specific criteria for the codification of tumor response evaluation. In 1994, several organizations involved in clinical research combined forces to tackle the review of these criteria on the basis of the experience and knowledge acquired since then. After several years of intensive discussions, a new set of guidelines is ready that will supersede the former criteria. In parallel to this initiative, one of the participating groups developed a model by which response rates could be derived from unidimensional measurement of tumor lesions instead of the usual bidimensional approach. This new concept has been largely validated by the Response Evaluation Criteria in Solid Tumors Group and integrated into the present guidelines. This special article also provides some philosophic background to clarify the various purposes of response evaluation. It proposes a model by which a combined assessment of all existing lesions, characterized by target lesions (to be measured) and nontarget lesions, is used to extrapolate an overall response to treatment. Methods of assessing tumor lesions are better codified, briefly within the guidelines and in more detail in Appendix I. All other aspects of response evaluation have been discussed, reviewed, and amended whenever appropriate.

cis-Diamminedichloroplatinum(II)-induced DNA adducts in peripheral leukocytes from seven cancer patients: quantitative immunochemical detection of the adduct induction and removal after a single dose of cis-diamminedichloroplatinum(II).

The same four platinum-containing products identified in nucleolytic digests of DNA treated with cisplatin (cisDDP) in vitro now have been shown to be present in digested DNA originating from human cells after in vivo exposure. The immunochemical detection of these products at the fmol level became possible by the application of an existing and two newly raised rabbit antisera with specificities towards the various cisDDP-DNA derived products. In DNA isolated from white blood cells of a number of cancer patients treated with the drug for the first time, intrastrand cross-links on pGpG base sequences appeared to be the main adduct, followed by the intrastrand cross-links on pApG sequences, interstrand cross-links, and/or intrastrand cross-links on two guanines separated by one or more bases and a very low amount of monofunctionally bound cisDDP to guanine; typical proportions were 65, 22, 13, and less than 1%, respectively. The induction and removal of the main adduct, the intrastrand cross-link on pGpG sequences, have been studied in DNA from blood samples of six male patients after their first cisDDP treatment. The results indicate that the susceptibility of blood cells to cisDDP-DNA adduct formation can show strong individually determined differences. From the data it is also clear that a substantial part of the adducts is removed within the first 24 h after the cisDDP-infusion.

Pharmacology of 5'-deoxy-5-fluorouridine in patients with resistant ovarian cancer.

The pharmacokinetics of the new fluoropyrimidine 5'-deoxy-5-fluorouridine (5'-dFUrd) was investigated in twelve patients. The kinetics of the main metabolite 5-fluorouracil (5-FUra) was studied in eight patients and those of 5,6-dihydro-5-fluorouracil (5-FUraH2) in five patients. The patients participated in a Phase II study performed to investigate the response rate of 5'-dFUrd in advanced ovarian cancer. The pharmacokinetic data were compared with the clinical effects of the drug. The parent drug and 5-FUra were measured in both plasma and urine by high performance liquid chromatography. 5-FUraH2 concentrations in plasma were determined by capillary gas chromatography using electron capture detection and nitrogen-phosphorus specific detection. Several pharmacokinetic parameters such as elimination half-life, mean residence time, and steady state volumes of distribution are presented for 5'-dFUrd, 5-FUra, and 5-FUraH2. Two patients showed a partial response, four had stable disease, and five had progressive disease; one patient died due to myelotoxicity. The severity of the side effects correlated with the mean residence times of 5'-dFUrd and 5-FUra. Low pretreatment serum creatinine clearance (due to renal impairment) correlated with low renal excretion of 5'-dFUrd and a long mean residence time of 5'-dFUrd with the sum of observed toxicity. However, the extent of degradation of 5-FUra to 5-FUraH2 may also be related to the severity of the toxicity of 5'-dFUrd.

cis-diamminedichloroplatinum(II)-resistant sublines derived from two human ovarian tumor cell lines.

In two human ovarian tumor cell lines, resistance to cis-diamminedichloroplatinum(II) (CDDP) was induced by continuous exposure of the parental lines to an increasing CDDP concentration in the culture medium. In contrast, a six times repeated pulse exposure of 6.7 microM or 16.7 microM CDDP for 1 h did not result in a cell line that showed a higher survival in CDDP-containing medium. The ID50 value for CDDP was seven to eight times higher for the resistant lines and those lines were able to grow at 3.3 microM CDDP. The induced resistance was stable during at least 25 doubling times. The CDDP-resistant sublines showed cross-resistance to the CDDP-analogues cis-diammine-1,1-cyclobutane-dicarboxylateplatinum(II) and cis-dichlorobis(isopropylamine)-trans-dihydroxyplatinum(IV) indicating that resistance to the different platinum compounds is generated by a common mechanism. The resistant sublines were also cross-resistant to mitomycin C and melphalan. The degree of cross-resistance for the tested drugs varied widely between the two cell lines. Resistance to CDDP was clearly correlated to decreased amounts of platinum in the resistant cells as compared to the sensitive cells. The amplification and expression of genes encoding proteins that had been shown to be involved in multidrug resistance, e.g., the Mr 170,000 P-glycoprotein was also studied. No amplification or overexpression of these genes could be shown in the resistant cell lines.

Kinetics of the formation and removal of cisplatin-DNA adducts in blood cells and tumor tissue of cancer patients receiving chemotherapy: comparison with in vitro adduct formation.

During chemotherapy with a cisplatin-containing combination of drugs, 217 blood samples from 30 cancer patients were analyzed for the presence of the main cisplatin-DNA adduct cis-Pt(NH3)2d(pGpG) (Pt-GG). Cisplatin was administered during 3-h infusions on each of 5 consecutive days, resulting in increasing adduct levels which, on the average, were about twice as high after the fifth as after the first infusion. Higher levels were found in blood samples of patients who received the same total amount of cisplatin in one single 3-h infusion. No significant differences in adduct levels were found during first and repeated courses. The nonlinear dependence of adduct levels on total dose can be attributed to removal of adducts. At 21 h after a very first cisplatin infusion 76% of the adducts were removed. Lower percentages of removal were observed over the 21-h periods following the fourth and fifth infusions of 5-day courses (49 and 53%, respectively). After the initial 21 h the removal of adducts continued, albeit at a slower rate. Substantial interindividual variation was found in the adduct levels, which did correlate with the levels obtained after in vitro cisplatin treatment of blood samples from the same patients but not with their age or gender. Testicular cancer patients with complete tumor response showed higher adduct levels in their blood than those with partial response or progressive disease. When blood samples from 8 healthy volunteers were treated with cisplatin in vitro, the person-to-person variation in adduct levels and the intraindividual variation observed over a 2-year period were found to be in the same range, which was narrower than that observed with samples from treated patients. In vitro studies with human blood showed that the formation of the Pt-GG adduct is proportional to cisplatin concentration and complete after about 1 hour. In some of the in vivo and in vitro cisplatin-treated blood samples, all 4 known platinum-DNA adducts were determined. In all cases Pt-GG was by far the major adduct, and no significant differences were observed with respect to the relative amounts of the 4 adducts. Similar adduct ratios were found in DNA from a testicular tumor obtained from a patient who underwent orchidectomy; the Pt-GG adduct level was about 10-fold higher than that in his blood cells.

Multivariate analysis of prognostic factors in patients with disseminated nonseminomatous testicular cancer: results from a European Organization for Research on Treatment of Cancer Multiinstitutional Phase III Study.

Univariate and multivariate linear logistic regression analyses of potential prognostic variables have been performed for 163 patients with disseminated nonseminomatous testicular cancer, treated with cisplatin, vinblastine, and bleomycin in a multicenter study of the European Organization for Research on Treatment of Cancer Genito-Urinary Tract Cancer Cooperative Group. With a multivariate analysis, four prognostic groups with complete responder rates of 100, 89, 41, and 18%, respectively, were identified based on three prognostic factors: trophoblastic elements in the primary tumor, serum concentration of alpha-fetoprotein, and lung metastases by size and number. However, with a univariate analysis the logarithm of the beta subunit of human chorionic gonadotrophin (BHCG) was the single most important factor. This model aids the physician in selecting prospectively good risk patients who are candidates for low toxicity chemotherapy and poor risk patients with whom innovative treatment should be attempted.

Resistance patterns between cis-diamminedichloroplatinum(II) and ionizing radiation.

Cross-resistance between cis-diamminedichloroplatinum(II) (CDDP) and radiation resistance has been suggested from clinical and experimental data (C. T. Coughlin and R. C. Richmond, Semin. Oncol., 16: 31-43, 1989). To determine whether cross-resistance patterns between both cytotoxic approaches exist, resistance against CDDP and ionizing radiation was induced separately in human ovarian cancer cells in a cross-over design. Subsequently sensitivity changes were determined for both treatment modalities. CDDP resistance was induced previously (P. J. Kuppen et al., Cancer Res., 48: 3355-3359, 1988), and resistant cells were grown at three different levels of CDDP:0 ng/ml; 250 ng/ml; and 500 ng/ml. Resistance with resistance factor (RF) 3.4 to 5.1 proved to be stable, since withdrawal of CDDP pressure for at least 6 mo did not alter resistance patterns. CDDP-resistant cells also demonstrated stable resistance against ionizing radiation, with RF ranging from 1.7 to 2.0. The resistance patterns could not be explained by differences in growth kinetics and DNA content. Resistance to ionizing radiation was induced in the same human ovarian cancer cells as used for CDDP resistance studies. Exposure with 1.5 Gy of intermittent irradiation during 6 mo, at time intervals of 48 h, resulted in cells which were able to grow under chronic ionizing radiation pressure. RF was 2.0; the resistance was lost after 6 mo of culturing without ionizing radiation pressure. With intermittent radiation doses of 0.5 and 1.0 Gy, no significant resistance could be induced. Cells intermittently exposed to 0.5, 1.0, and 1.5 Gy during 6 mo demonstrated increased sensitivity to CDDP, with 0.22 less than RF less than 0.43. Increased sensitivity was associated with proportionally increased formation of the platinum-DNA adducts. Differences in sensitivity for both ionizing radiation and CDDP were lost after 6 mo of culturing without radiation pressure; therefore, resistance toward ionizing radiation and, likewise, the increased sensitivity to CDDP, were judged to be unstable. In conclusion, data of the present study demonstrated that development of stable resistance to CDDP is associated with development of stable resistance to ionizing radiation in human ovarian cancer. Contrastingly, increased sensitivity to CDDP was found when resistance against irradiation was induced in the same cells.

Predictability of the survival of patients with advanced ovarian cancer.

Based on material from two clinical trials performed by The Netherlands Joint Study Group for Ovarian Cancer, we constructed a prognostic index (PI) with considerable predictive power for long-term survival of patients treated with cytotoxic combination chemotherapy including cisplatin. The pretreatment characteristics needed for the calculation of the PI are the Karnofsky index, the site of metastases expressed as the International Federation of Gynecology and Obstetrics (FIGO) stage, the size of residual tumor, the Broders' grade, and the presence of ascites. In the subgroup comprising the 10% of the patients with the best prognosis, 4-year survival was 75%, whereas all of the patients in the subgroup comprising the 10% with the poorest prognosis died within 4 years, which illustrates the large variability of the prognosis among patients. The PI was found to retain its value after response was achieved. The information provided by the PI can be expected to be useful in treatment planning and for proper stratification of patients in clinical trials.

A comparison of two short intensive adjuvant chemotherapy regimens in operable osteosarcoma of limbs in children and young adults: the first study of the European Osteosarcoma Intergroup.

PURPOSE: A randomized pilot study was undertaken to assess the acute and chronic toxicities of two short intensive chemotherapy regimens, and to evaluate the feasibility of conservative surgery in this setting. Additional aims were to determine the clinical and radiologic response and the degree of histologic necrosis after chemotherapy. With extension of the study, eventual accrual was sufficient to compare disease-free survival (DFS) and overall survival (OS). PATIENTS AND METHODS: Between July 1983 and December 1986, the European Osteosarcoma Intergroup (EOI) entered 198 eligible patients with classic high-grade extremity osteosarcoma onto a randomized trial that compared doxorubicin (DOX) 25 mg/m2/d times three, intravenous (IV) bolus plus cisplatin (CDDP) 100 mg/m2, 24 hour infusion, every 3 weeks times six; the same combination was preceded 10 days earlier by high-dose methotrexate (HDMTX) 8 g/m2, 6-hour infusion, every 4.5 weeks times four. In the majority of patients (179), chemotherapy was commenced after biopsy; definitive surgery was scheduled at 9 weeks in both groups. RESULTS: Toxicities for both regimens did not differ substantially from those that occurred in other trials of adjuvant chemotherapy in osteosarcoma. Local recurrence (9%) and surgical complications (18%) after conservative surgery were acceptable. With a median follow-up of 53 months, DFS at 5 years is superior (P = .02) for DOX/CDDP, 57% versus 41%, although OS, 64% versus 50%, is not different significantly (P = .10). In a subset of 66 patients for whom pathologic data on the resected specimen were available, DFS (P = .003) and OS (P = .008) were better for those who demonstrated > or = 90% necrosis. CONCLUSION: A brief intensive chemotherapy regimen of DOX/CDDP has produced excellent long-term results, which are similar to those that have been achieved in cooperative group studies of longer, more complex multiagent chemotherapy, and provide the basis for a direct comparison in the next EOI study.

Prognostic factors for the outcome of chemotherapy in advanced soft tissue sarcoma: an analysis of 2,185 patients treated with anthracycline-containing first-line regimens--a European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group Study.

PURPOSE: A total of 2,185 patients with advanced soft tissue sarcomas who had been treated in seven clinical trials investigating the use of doxorubicin- or epirubicin-containing regimens as first-line chemotherapy were studied in this prognostic-factor analysis. PATIENTS AND METHODS: Overall survival time (median, 51 weeks) and response to chemotherapy (26% complete response or partial response) were the two end points. The cofactors were sex; age; performance status; prior therapies; the presence of locoregional or recurrent disease; lung, liver, and bone metastases at the time of entry onto the trial; long time period between the initial diagnosis of sarcoma and entry onto the study; and histologic type and grade. RESULTS: Univariate analyses showed (a) a significant, favorable influence of good performance status, young age, and absence of liver metastases on both survival time and response rate, (b) a significant, favorable influence of low histopathologic disease grade on survival time, despite a significantly lower response rate, (c) increased survival time for patients with a long time period between the initial diagnosis of sarcoma and entry onto the study, despite equivalent response rates, and (d) increased survival time with liposarcoma or synovial sarcoma, a decreased survival time with malignant fibrous histiocytoma, a lower response rate with leiomyosarcoma, and a higher response rate with liposarcoma (P < .05 for all log-rank and chi2 tests). The Cox model selected good performance status (P < .0001), absence of liver metastases (P = .0001), low histopathologic grade (P = .0002), long time lapse since initial diagnosis (P = .0004), and young age (P = .0045) as favorable prognostic factors of survival time. The logistic model selected absence of liver metastases (P < .0001), young age (P = .0024), high histopathologic grade (P = .0051), and liposarcoma (P = .0065) as favorable prognostic factors of response rate. CONCLUSION: This analysis demonstrates that for advanced soft tissue sarcoma, response to chemotherapy is not predicted by the same factors as is overall survival time. This needs to be taken into account in the interpretation of trials assessing the value of new agents for this disease on the basis of response to treatment.

High-dose versus low-dose vinblastine in cisplatin-vinblastine-bleomycin combination chemotherapy of non-seminomatous testicular cancer: a randomized study of the EORTC Genitourinary Tract Cancer Cooperative Group.

Two hundred fourteen patients with disseminated non-seminomatous testicular cancer were randomized to receive induction chemotherapy with cisplatin, vinblastine, and bleomycin (PVB). The randomization was for vinblastine 0.4 mg/kg/cycle or 0.3 mg/kg/cycle. The complete response (CR) rates to both regimens were identical: 68% and 71%, respectively. In addition, there was no significant difference in disease-free and overall survival. There was a significant decrease in the incidence of WBC nadirs below 1,000/microL: 29% and 13%, respectively (P = .01). Of the non-hematologic toxicities, there was a significant reduction in the incidence of mucositis: 53% and 37%, respectively (P = .006). The major prognostic factor was tumor volume. This study confirms that vinblastine 0.3 mg/kg/cycle in PVB chemotherapy is as effective and less toxic than vinblastine 0.4 mg/kg/cycle.

Randomized trial comparing two combination chemotherapy regimens (CHAP-5 v CP) in advanced ovarian carcinoma.

One hundred ninety-one patients with advanced epithelial ovarian carcinoma were treated with either a combination of doxorubicin and a five-day course of cisplatin alternating with cyclophosphamide and hexamethylmelamine orally for 14 days (CHAP-5) or cyclophosphamide and cisplatin both administered intravenously (IV) on a single day at 3-week intervals (CP). At a median follow-up time of 45 months, treatment with each of these combinations resulted in the same remission rates (80% and 74%, respectively) and exactly the same progression-free survival and overall survival (median, 26 months). Despite adequate hydration, more renal toxicity was encountered in the CP-treated patients than in those who received CHAP-5. Disabling neurotoxicity and severe myelosuppression were encountered more frequently in the patients treated with CHAP-5. Because the toxicity was lower and CP treatment required shorter hospitalization, the single-day regimen was considered preferable for future use. The Karnofsky index was the only independent predictor for response, whereas both this index and the size of residual tumor before chemotherapy were predictive of survival. After correcting for other prognostic factors, it was determined that tumor size associated with improved survival was less than 1 cm. The site of metastases in International Federation of Gynecology and Obstetrics (FIGO) stage IV patients did not influence survival within this category. The results of this study confirm our previous findings that patients with microscopic remnants at second-look have a survival similar to that of patients who are histopathologically free of disease. This makes the significance of so-called pathologically confirmed complete remission questionable. The survival benefit of debulking surgery performed during chemotherapy seems only minimal for patients in whom debulking has already been attempted before treatment. Like others, we have found the CP regimen to have a good therapeutic index.

Ten-year survival and late sequelae in testicular cancer patients treated with cisplatin, vinblastine, and bleomycin.

This 10-year follow-up study of 91 patients with disseminated testicular nonseminomatous cancer, treated with cisplatin, vinblastine, and bleomycin (PVB) induction chemotherapy and vinblastine plus bleomycin maintenance chemotherapy for a planned period of 2 years, shows a 63% cure rate. The predominant long-term sequelae are neurological and sexual dysfunction in 68% and 40% of patients, respectively. Two patients died of myocardial infarction. Sixteen percent of patients developed hypertension, 23% Raynaud's phenomenon, and 25% ototoxicity. Despite the long-term side effects, 90% of the patients who responded to a questionnaire are fully employed. This study shows that the maintenance chemotherapy has contributed to the incidence and/or degree of neurotoxicity, hypertension, and renal function disturbance.

Randomized phase III trial of high-dose-intensity methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) chemotherapy and recombinant human granulocyte colony-stimulating factor versus classic MVAC in advanced urothelial tract tumors: European Organization for Research and Treatment of Cancer Protocol no. 30924.

PURPOSE: This randomized trial evaluated antitumor activity of and survival asociated with high-dose-intensity chemotherapy with methotrexate, vinblastine, doxorubicin, and cisplatin (MVAC) plus granulocyte colony-stimulating factor (HD-MVAC) versus MVAC in patients with advanced transitional-cell carcinoma (TCC). PATIENTS AND METHODS: A total of 263 patients with metastatic or advanced TCC who had no prior chemotherapy were randomized to HD-MVAC (2-week cycles) or MVAC (4-week cycles). RESULTS: Using an intent-to-treat analysis, at a median follow-up of 38 months, on the HD-MVAC arm there were 28 complete responses (CRs) (21%) and 55 partial responses (PRs) (41%), for an overall response of 62% (95% confidence interval [CI], 54% to 70%). On the MVAC arm, there were 12 CRs (9%) and 53 PRs (41%), for an overall response of 50% (95% CI, 42% to 59%). The P value for the difference in CR rate was.009; and for the overall response, it was.06. There was no statistically significant difference in survival (P =.122) or time to progression (P =.114). Progression-free survival was significantly better with HD-MVAC (P=.037; hazard ratio.75; 95% CI.58 to.98). The median progression-free survival time was 9.1 months on the HD-MVAC arm versus 8.2 months on the MVAC arm. The 2-year progression-free survival rate was 24.7% for HD-MVAC (95% CI, 17.1% to 32.3%) versus 11.6% for MVAC (95% CI, 5.9% to 17.4%). CONCLUSION: With HD-MVAC, it was possible to deliver twice the doses of cisplatin and doxorubicin in half the time, with fewer dose delays and less toxicity. Although a 50% difference in median overall survival was not detected, a benefit was observed in progression-free survival, CR rates, and overall response rates with HD-MVAC.

Population pharmacokinetics/pharmacodynamics of docetaxel in phase II studies in patients with cancer.

PURPOSE: The population pharmacokinetic/pharmacodynamic (PK/PD) approach was prospectively integrated in the clinical development of docetaxel to assess the PK profile in a large population of patients and investigate systemic exposure as a prognostic factor for clinical outcome. PATIENTS AND METHODS: PK analysis was performed at first course in 24 phase II studies of docetaxel monotherapy using four randomized limited-sampling schedules. Bayesian estimates of clearance (CL), area under the concentration-time curve (AUC), and peak and duration of plasma levels greater than threshold levels were used as measures of exposure. PD data included for efficacy, response rate, time to first response, and time to progression (TTP) in breast cancer and non-small-cell lung cancer (NSCLC), and for toxicity, grade 4 neutropenia, and febrile neutropenia at first course and time to onset of fluid retention. PK/PD analysis was conducted using logistic and Cox multivariate regression models. RESULTS: PK protocol implementation was successful. Most of the patients registered (721 of 936, 77%) were sampled and 68% were assessable for PK (640 patients). First-course docetaxel AUC was a significant predictor (P = .0232) of TTP in NSCLC (n = 151). Docetaxel CL was a strong independent predictor (P < .0001) of both grade 4 neutropenia and febrile neutropenia (n = 582). Cumulative dose was the strongest predictor (P < .0001) of the time to onset of fluid retention (n = 631). However, the duration of exposure over 0.20 micromol/L (0.16 microg/mL) at first course was an independent predictor (P = .0029). Few patients (n = 25, 4%) received the recommended dexamethasone premedication. CONCLUSION: First-course docetaxel PK is a predictor of first-course hematologic toxicity, but also of fluid retention, which is cumulative in nature. Patients with elevated hepatic enzymes have a 27% reduction in docetaxel CL and are at a higher risk of toxicity. A starting dose of 75 mg/m2 is currently being evaluated in this population. Prospective implementation of large-scale population PK/PD evaluation is feasible in early drug development and this approach generates clinically relevant findings.

Sensitive and specific quantification of the anticancer agent ZD1839 (Gefitinib) in plasma by on-column focusing capillary liquid chromatography-tandem mass spectrometry.

The development of an on-column focusing gradient capillary LC method coupled to tandem mass spectrometry (quadrupole-linear ion trap) for the quantitative determination of the anticancer agent ZD1839 (Gefitinib, Iressa) in blood plasma is described. Plasma samples (0.2 ml) were extracted with methyl tert-butyl ether. The analytes of interest, ZD1839 and the internal standard [(2)H8]ZD1839 (ZD1839-d8) were eluted on a 50 mm x 1 mm, 5 microm particle size, capillary ODS Hypersil column using an aqueous ammonium acetate gradient at 40 microl/min. Mass spectrometric detection was performed by a Q-Trap tandem mass spectrometer with electrospray positive ionisation, and monitored in the multiple reaction monitoring transitions 447 >128 and 455 >136, respectively. The limit of quantification of ZD18395 was 0.1 ng/ml. The method proved to be robust, allowing quantification of ZD1839 with sufficient precision, accuracy and sensitivity.

A Phase I study of capecitabine in combination with oral leucovorin in patients with intractable solid tumors.

Capecitabine (Xeloda) is a novel rationally designed fluoropyrimidine carbamate. It passes through the intestinal mucosal membrane intact and is subsequently activated by a cascade of three enzymes resulting in preferential release of 5-fluorouracil (5-FU) at the tumor site. Preclinical studies indicated an enhancement of the therapeutic index when capecitabine was combined with leucovorin. This Phase I trial was designed to determine the safety profile, maximal tolerated dose, and pharmacokinetic profile of the combination of capecitabine plus a fixed dose of p.o. leucovorin (60 mg/day) during administration to patients with refractory advanced cancers. The intention was to administer both drugs continuously, but the starting dose of capecitabine was also the maximum tolerated dose (1004 mg/m2/day) in six patients treated with this regimen. A cycle of treatment was then redefined as leucovorin and capecitabine given p.o., twice daily for 2 consecutive weeks followed by a 1-week rest period. Capecitabine doses from 1004 mg/m2/day to 2510 mg/m2/day were evaluated with the intermittent schedule over approximately 80 courses in an additional 25 patients. The dose-limiting toxicities that defined the maximum tolerated dose at 2000 mg/m2/day were diarrhea, nausea, vomiting, and palmar plantar erythrodysesthesia. The recommended Phase II dose using this schedule was 1650 mg/m2/day of capecitabine plus leucovorin 60 mg/day. Plasma concentrations of capecitabine, intermediate metabolites, and 5-FU were measured in 26 patients on days 1 and 14 of therapy. The pharmacokinetics of capecitabine were characterized by rapid GI absorption, with Cmax at 1 h, followed by conversion to active drug. The coadministration of leucovorin had no effect on the pharmacokinetics of capecitabine. Two patients with colorectal cancer, both previously treated with 5-FU, had partial responses. Phase II studies have confirmed the promising antitumor activity of this drug, and capecitabine is currently in Phase III evaluation.

PNU-145156E, a novel angiogenesis inhibitor, in patients with solid tumors: a phase I and pharmacokinetic study.

Our aim was to establish, in patients with solid tumors, the dose-limiting toxicity, maximum tolerated dose (MTD), and pharmacology of PNU-145156E, a new sulfonated distamycin A derivative that blocked circulating angiogenesis-promoting growth factors in animal studies and exhibited an antitumor effect in murine solid tumors. In a Phase I study, PNU-145156E was administered i.v. every 6 weeks. Included were patients with solid tumors; an Eastern Cooperative Oncology Group performance score