Plasma activity of prolyl endopeptidase in relation to psychopathology during immunotherapy with IFN-alpha in patients with renal cell carcinoma.

Abnormal activity in peripheral blood of the cytosolic enzyme prolyl endopeptidase (PEP, EC 3.4.21.26, post prolyl cleaving enzyme, prolyl oligopeptidase) has been found in patients with a variety of psychiatric disorders, most consistently in mood disorders. Mood disturbance is a well-known side effect of immunotherapy with interferon-alpha (IFN-alpha). Earlier, we documented a decrease in serum PEP activity in the first 4 weeks of treatment with IFN-alpha. In 24 patients (16 men, 8 women, median age 60.5 years, range 47-72 years) with metastatic renal cell carcinoma (RCC), psychiatric assessment and blood sampling were performed before and at 4 and 8 weeks and at 6 months after initiation of treatment with IFN-alpha. No episodes of depression were observed, and the sum score and the scores on the subscales for depression and hostility of the Symptom Check List-90 (SCL-90) did not change during follow-up, whereas the anxiety scores were somewhat lower at 4 and 8 weeks compared with baseline. No change in plasma PEP activity and no relationships between change in psychiatric parameters and change in plasma PEP activity were found. As more subtle relationships between PEP activity and psychiatric status could have easily been obscured, a role for PEP in the pathophysiology of IFN-alpha-induced mood disturbance can neither be confirmed nor excluded.

Serum proteomic patterns for ovarian cancer monitoring.

We set out to discover ovarian cancer biomarkers useful for monitoring progression during and after chemotherapy and possibly for diagnosis. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry was used to create serum protein profiles of ovarian cancer patients before chemotherapy or at progression (n = 51) (trial initiated by the Gynecological Cancer Cooperative Group of the European Organization for Research and Treatment of Cancer trial) that were compared with those of healthy individuals (n = 31). In addition, sera profiles from ovarian cancer patients after chemotherapy (n = 12) were compared with those of ovarian cancer patients at progression (n = 24). One of the discovered biomarkers was identified and subsequently confirmed and validated using enzyme-linked immunosorbent assay (ELISA). Eight primary (sens = 94%, spec = 97%, P < 0.0001) and seven progression tumor biomarkers (sens = 91%, spec = 97%, P < 0.0001) were discovered. In addition, we discovered eight potential progression monitoring biomarkers (sens = 75%, spec = 83%, P = 0.0008) of which one, a biomarker of 11.7 kd, was further identified as serum amyloid A1. Independent validation (ELISA) showed an elevated expression of this protein at relapse in four of the seven ovarian cancer patients tested. Combining the eight newly discovered progression monitoring biomarkers with CA125 resulted in a clear increase of the sensitivity (91-100%). These biomarkers, in combination with for instance CA125, should be validated in large ovarian cancer and control groups. The resulting multimarker assay could be suitable for disease monitoring during and after therapy and might also be useful for ovarian cancer screening.

Adverse effect on bone marrow protection of prechemotherapy granulocyte colony-stimulating factor support.

BACKGROUND: Increased proliferation of endogenous bone marrow progenitor cells in response to the administration of hematopoietic growth factors, followed by reduced cell cycling or entrance of the cells into a quiescent state upon withdrawal of the growth factors, may have clinically relevant effects on the tolerance of the hematopoietic system to subsequent myelotoxic treatments. PURPOSE: We investigated the ability of granulocyte colony-stimulating factor (G-CSF) to protect progenitor cells in the bone marrow of cancer patients from the toxic effects of subsequent treatments with chemotherapeutic agents. METHODS: Thirty-six patients with histologically documented, locally advanced or metastatic breast cancer were randomly assigned to receive doxorubicin once every 3 weeks at a dose of 75 mg/m2 and cyclophosphamide at a dose of 1000 mg/m2, with G-CSF administered either before and after chemotherapy (18 patients) or after chemotherapy only (18 patients). For prechemotherapy administration of G-CSF, recombinant human methionyl (r-met Hu) G-CSF was administered subcutaneously to patients twice per day for 5 days at a dose of 5 micrograms/kg, with the last dose given 48 hours before the start of chemotherapy. For postchemotherapy administration of G-CSF, r-met Hu G-CSF was administered subcutaneously to patients once per day for 7 days at a dose of 5 micrograms/kg, with the first dose given 24 hours after chemotherapy. RESULTS: The incidence or the duration of grade 4 neutropenia was not reduced in all patients by the use of prechemotherapy G-CSF; the incidence over all cycles of chemotherapy was 74% for patients treated with prechemotherapy and postchemotherapy G-CSF and 66% for patients treated with postchemotherapy G-CSF only (two-sided P, adjusted for dose = .21) and the median duration in both treatment arms was 3 days (two-sided P = .19). Unexpectedly, the incidence of grades 3 and 4 thrombocytopenia was much greater in patients who received prechemotherapy G-CSF compared with those who did not (54% versus 6%, respectively, over all chemotherapy cycles; two-sided P, adjusted for dose < .001). No difference in the decrease in hemoglobin level (adjusted for red blood cell transfusions) between patients in the two treatment arms was observed. CONCLUSIONS AND IMPLICATIONS: No beneficial effects were associated with the administration of G-CSF to cancer patients prior to chemotherapy. The observation of more severe thrombocytopenia in patients treated with prechemotherapy G-CSF led us to conclude that the proliferation of progenitor cells was still increased 48 hours after the last dose of G-CSF and that the administration of chemotherapy at or within this time period actually worsens the toxic effects on bone marrow. This result has important ramifications for the design of clinical cancer treatment protocols, especially those that involve shortened intervals between cycles of chemotherapeutic agent administration.

Regression of advanced ovarian carcinoma by intraperitoneal treatment with autologous T lymphocytes retargeted by a bispecific monoclonal antibody.

BACKGROUND: The high frequency of relapse after induction chemotherapy of advanced ovarian carcinoma calls for new therapeutic approaches. Lysis of ovarian carcinoma cells can be achieved by retargeting of T lymphocytes using F(ab')2 fragments of the bispecific monoclonal antibody (MAb) OC/TR, which is directed to the CD3 molecule on T lymphocytes and to the folate receptor on ovarian carcinoma cells. PURPOSE: Our purpose was to assess in ovarian carcinoma patients the antitumor activity of in vitro-activated autologous peripheral blood T lymphocytes retargeted with OC/TR. METHODS: Patients with epithelial ovarian cancer (International Federation of Gynecology and Obstetrics stages III and IV) meeting specific criteria were eligible to enter a phase II immunotherapy trial. Before immunotherapy, the 28 patients who entered the trial underwent laparotomy to reduce their tumor load and to allow measurement of all indicator lesions. They then received two cycles of five daily intraperitoneal infusions of autologous in vitro activated peripheral blood T lymphocytes retargeted with OC/TR plus recombinant interleukin 2 (IL-2) with (n = 11) or without (n = 17) a second daily infusion of OC/TR F(ab')2 and IL-2. Response to treatment could be assessed in 26 patients following explorative laparotomy; time to progression could be assessed in 27 patients. RESULTS: Seven patients had clinical evidence of progressive disease after treatment and therefore did not undergo laparotomy. Of the 19 patients evaluated by surgery and histology, three showed complete response, one showed complete intraperitoneal response with progressive disease in retroperitoneal lymph nodes, three showed partial response, seven had stable disease, and five had progressive disease. The overall intraperitoneal response rate was 27% (95% confidence interval [CI] = 10%-44%). The complete responses seen in three patients lasted 26 months in one patient, 23 months in the second, and 18 months in the third. Two patients were not assessable for response. One of these patients had bowel perforation during catheter removal, which precluded further evaluation. The second patient was positive only by cytologic examination before immunotherapy, was tumor free at laparotomy after immunotherapy, and remained so for the entire 21 months of follow-up, as determined by cytologic examination of random biopsy specimens. The median time to disease progression in the 15 assessable patients plus those who had stable disease was 11 months (95% CI = 6-18 months). Immunotherapy-related toxic effects included mild to moderate fever, nausea, emesis, and fatigue. Anti-mouse antibodies were detectable by the end of the treatment in 21 of 25 patients tested. CONCLUSIONS: Locoregional immunotherapy of ovarian cancer with bispecific MAb-retargeted T lymphocytes can result in tumor regression. Toxicity was mild to moderate and only transient. IMPLICATIONS: Improvement in systemic antitumor responses is needed before this approach can prove useful as adjunctive treatment following induction chemotherapy in patients with minimal residual disease.

Phase I and pharmacologic study of the novel indoloquinone bioreductive alkylating cytotoxic drug E09.

BACKGROUND: A novel bioreductive alkylating indoloquinone compound, E09 [3-hydroxy-5-aziridinyl-1-methyl-2-(1H-indole-4,7-indione)- prop-F128b-en-alpha-ol], has been shown to have distinct antitumor activity against solid tumors, excellent activity under hypoxic conditions, but no notable bone marrow toxicity in preclinical models. PURPOSE: A phase I study was carried out to determine the toxicity, maximum tolerated dose (MTD), pharmacology, and antitumor response of E09. METHODS: E09 was administered as a 5-minute intravenous infusion once every 3 weeks to 32 patients with solid tumors. The starting dose of 2.7 mg/m2 was one tenth of the mouse equivalent of lethal dose to 10% of animals (MELD10). Dose was escalated by 100% until the area under the curve (AUC) at the MELD10 was reached, following a Fibonacci-like schedule. The pharmacokinetics of E09 and its metabolite E05A with an open aziridine ring was determined using a new high-pressure liquid chromatographic method and noncompartmental calculation of kinetic parameters. The sigmoid Emax model was used to fit pharmacokinetic parameters to toxicity. The renal function and proteinuria were quantitated and were further evaluated by determining renal clearance ratios of immunoglobulin G (IgG) to albumin and pancreatic amylase to salivary amylase. RESULTS: The 32 patients were treated with a total of 85 assessable courses of E09. The dose-limiting toxicity was proteinuria, which was accompanied by sodium and water retention. All symptoms were reversible on day 15 except in two patients, who developed acute renal failure. The ratios of IgG to albumin and pancreatic amylase to salivary amylase suggested a loss of glomerular negative charge consistent with a minimal change glomerulopathy. The pharmacokinetics of E09 showed its rapid elimination from the central compartment but with wide interpatient variation in the overall disposition of the drug. Total plasma clearance of E09 ranged from 3.2 to 24 L/min. The AUC of E09 was linearly related to the administered dose. The relationship between the AUC and proteinuria was best fitted by the sigmoid Emax model (r = .98). In two patients with adenocarcinoma of unknown primary site and in a third patient with bile duct cancer, a partial response was observed. CONCLUSIONS: The MTD of E09 was determined to be 27 mg/m2. The standard approach of drug administration is considered unsuitable because of potential renal toxicity and wide variability in the pharmacokinetics of E09. Individual dose adjustments based on plasma concentration measurements are recommended to combine maximally achievable exposure with tolerable toxicity.

Risk of second malignant neoplasms among long-term survivors of testicular cancer.

BACKGROUND: We have quantified the site-specific risk of second malignant neoplasms among nearly 29,000 survivors (> or = 1 year) of testicular cancer, taking into account the histologic type of initial cancer and the primary therapy used to treat it. METHODS: The study cohort consisted of 28,843 men identified within 16 population-based tumor registries in North America and Europe; over 3300 men had survived more than 20 years. New invasive cancers were identified through a search of registry files. RESULTS: Second cancers were reported in 1406 men (observed-to-expected ratio [O/E] = 1.43; 95% confidence interval = 1.36-1.51), with statistically significant excesses noted for acute lymphoblastic leukemia (O/E = 5.20), acute nonlymphocytic leukemia (O/E = 3.07), melanoma (O/E = 1.69), non-Hodgkin's lymphoma (O/E = 1.88), and cancers of the stomach (O/E = 1.95), colon (O/E = 1.27), rectum (O/E = 1.41), pancreas (O/E = 2.21), prostate (O/E = 1.26), kidney (O/E = 1.50), bladder (O/E = 2.02), thyroid (O/E = 2.92), and connective tissue (O/E = 3.16). Overall risk was similar after seminomas (O/E = 1.42) or nonseminomatous tumors (O/E = 1.50). Risk of solid tumors increased with time since the diagnosis of testicular cancer, yielding an O/E = 1.54 (O = 369) among 20-year survivors (two-sided P for trend = .00002). Secondary leukemia was associated with both radiotherapy and chemotherapy, whereas excess cancers of the stomach, bladder, and, possibly, pancreas were associated mainly with radiotherapy. CONCLUSIONS: Men with testicular cancer continue to be at significantly elevated risk of second malignant neoplasms for more than two decades following initial diagnosis. Patterns of excess second cancers suggest that many factors may be involved, although the precise roles of treatment, natural history, diagnostic surveillance, and other influences are yet to be clarified.

Radioimmunodetection in rhabdo- and leiomyosarcoma with 111In-anti-myosin monoclonal antibody complex.

In patients with rhabdo- and leiomyosarcoma a radioimmunodiagnostic study was performed with 111In labeled F(ab) fragments of a monoclonal antibody against myosin. Eight patients with rhabdomyosarcoma and 18 patients with leiomyosarcoma were studied. Scanning was performed at 4, 24, and 48 h after administration of 74 MBeq of the antibody complex. A high uptake with a tumor:background ratio of 10:1 was observed in several patients with rhabdomyosarcoma but the results were less accurate in leiomyosarcoma.

Exogenous interleukin 2 recruits in vitro lymphokine-activated killer activity by in vivo activated lymphocytes.

Cryopreserved and thawed lymphocytes can be used instead of fresh lymphocytes to avoid test-to-test variability in studies of fluctuations of natural killer (NK) and lymphokine-activated killer (LAK) activities as a function of time. We investigated the effects of 1-h versus 18-h resting of lymphocytes on their lytic activities, because the process of cryopreservation and thawing decreases NK and LAK activities. Lymphocytes from renal cell cancer patients receiving adoptive immunotherapy were studied. An 18-h versus 1-h resting period led to a significant increase in NK activity but had no significant effect on LAK activity. The presence of 1200 IU/ml interleukin 2 (IL-2) in the medium 1 h prior to and during the cytotoxicity (CTX) assay increased in vivo and in vitro IL-2-induced LAK activities. This phenomenon has been interpreted as IL-2 dependency of effector lymphocytes (J.A. Hank, P.C. Kohler, G. Weil-Hillman, N. Rosenthal, K. H. Moore, B. Storer, D. Minkoff, J. Bradshaw, R. Bechhofer, and P. M. Sondel. Cancer Res., 48: 1965-1971, 1988). We performed kinetic studies to assess the role of effector lymphocyte recruitment in these experiments. LAK activity was tested in the presence or absence of IL-2 during preincubations and CTX assays varying between 0 and 120 min. These kinetic studies showed that effector lymphocyte recruitment indeed contributed to the increased level of LAK activity when IL-2 was added to the CTX assay. A minimal incubation period of 30 min was required to detect recruitment of lymphocytes. Effector lymphocytes could be recruited for periods varying between 90 and greater than 240 min, depending on the lymphocyte donor. We conclude that: (a) in vitro, IL-2-mediated recruitment of lymphocytes due to presence of IL-2 in the CTX assay may lead to an overestimate of the actual LAK activity; and (b) in vivo, prolonged IL-2 infusion after the administration of activated lymphocytes seems warranted in order to recruit maximal levels of effector lymphocytes with LAK activity.

Cremophor EL-mediated alteration of paclitaxel distribution in human blood: clinical pharmacokinetic implications.

We have determined the in vitro and in vivo cellular distribution of the antineoplastic agent paclitaxel (Taxol) in human blood and the influence of Cremophor EL (CrEL), the vehicle used for i.v. drug administration. In the absence of CrEL, the blood:plasma concentration ratio was 1.07+/-0.004 (mean+/-SD). The addition of CrEL at concentrations corresponding to peak plasma levels achieved after the administration of paclitaxel (175 mg/m2 i.v. over a 3-h period; ie., 0.50%) resulted in a significant decrease in the concentration ratio (0.690+/-0.005; P < 0.05). Kinetic experiments revealed that this effect was caused by reduced erythrocyte uptake of paclitaxel by polyoxyethyleneglycerol triricinoleate, the major compound present in CrEL. Using equilibrium dialysis, it was shown that the affinity of paclitaxel for tested matrices was (in decreasing order) CrEL > plasma > human serum albumin, with CrEL present at or above the critical micellar concentration (approximately 0.01%). Our findings in the present study demonstrate a profound alteration of paclitaxel accumulation in erythrocytes caused by a trapping of the compound in CrEL micelles, thereby reducing the free drug fraction available for cellular partitioning. It is proposed that the nonlinearity of paclitaxel plasma disposition in patients reported previously should be reevaluated prospectively by measuring the free drug fractions and whole blood:plasma concentration ratios.

SKY1 is involved in cisplatin-induced cell kill in Saccharomyces cerevisiae, and inactivation of its human homologue, SRPK1, induces cisplatin resistance in a human ovarian carcinoma cell line.

The therapeutic potential of cisplatin, one of the most active and widely used anticancer drugs, is severely limited by the occurrence of cellular resistance. In this study, using budding yeast Saccharomyces cerevisiae as a model organism to identify novel drug resistance genes, we found that disruption of the yeast gene SKY1 (serine/arginine-rich protein-specific kinase from budding yeast) by either transposon insertion or one-step gene replacement conferred cellular resistance to cisplatin. Heterologous expression of the human SKY1 homologue SRPK1 (serine/arginine-rich protein-specific kinase) in SKY1 deletion mutant yeast cells restored cisplatin sensitivity, suggesting that SRPK1 is a cisplatin sensitivity gene, the inactivation of which could lead to cisplatin resistance. Subsequently, we investigated the role of SRPK1 in cisplatin sensitivity and resistance in human ovarian carcinoma A2780 cells using antisense oligodeoxynucleotides. Treatment of A2780 cells with antisense oligodeoxynucleotides directed against the translation initiation site of SRPK1 led to down-regulation of SRPK1 protein and conferred a 4-fold resistance to cisplatin. The human SRPK1 gene has not been associated with drug resistance before. Our new findings strongly suggest that SRPK1 is involved in cisplatin-induced cell kill and indicate that SRPK1 might potentially be of importance for studying clinical drug resistance.

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.

Parallel detection of transduced T lymphocytes after immunogene therapy of renal cell cancer by flow cytometry and real-time polymerase chain reaction: implications for loss of transgene expression.

We have started a phase I/II immunogene therapy study of metastatic renal cell cancer (RCC), using autologous T lymphocytes transduced ex vivo with a gene encoding a single-chain receptor based on the monoclonal antibody (mAb) G250 [scFv(G250)]. G250 recognizes carbonic anhydrase IX, which is overexpressed by RCC cells. We have developed and validated flow cytometric and real-time polymerase chain reaction (PCR) assays to quantitatively detect transduced T cells in patient blood. The flow assay was based on staining with the anti-G250 idiotype mAb NuH82 and showed a sensitivity of 0.06% scFv(G250)(1) cells within CD3(1) T cells. The real-time PCR method showed a sensitivity of 14 copies of scFv(G250) DNA per 100 ng of total DNA, which enabled detection of 0.008% scFv(G250)(1) T cells within leukocytes. Both assays were further validated for their specificity and reproducibility. When applied to blood samples from three RCC patients treated with intravenous infusions of scFv(G250)(1) T cells, the kinetics of scFv(G250)(1) T cell counts as detected by flow cytometry were similar to those detected by real-time PCR, although PCR allowed detection of transduced T cells over a longer period of time (i.e., for patient 3, 7 versus 32 days, respectively). Interestingly, follow-up studies of patient 3 demonstrated that the number of circulating scFv(G250)(1) T cells remained fairly constant during the first 7 days posttreatment, whereas the number of gene copies increased during the same period of time. These results suggest loss of scFv(G250) membrane expression on adoptive transfer, which would have important implications for the antitumor efficacy of this form of immunogene therapy.

Simple prognostic model to predict survival in patients with undifferentiated carcinoma of unknown primary site.

PURPOSE: We performed this study to identify prognostic factors in a subgroup of patients with carcinoma of unknown primary site treated with cisplatin combination chemotherapy. PATIENTS AND METHODS: Seventy-nine patients with poorly differentiated adenocarcinoma or undifferentiated carcinoma of unknown primary site were treated on two consecutive phase II chemotherapy protocols. The first protocol consisted of treatment with 3-week courses of cisplatin, etoposide, and bleomycin (BEP). In the second protocol, cisplatin was administered weekly combined with oral administration of etoposide (DDP/VP). To identify prognostic factors, univariate and multivariate analyses were conducted. RESULTS: In the univariate analysis, performance status, histology, liver or bone metastases, and serum levels of alkaline phosphatase and AST were significant variables to predict survival. In the multivariate analysis, performance status and alkaline phosphatase were the most important prognostic factors. CONCLUSION: Good-prognosis patients had a performance score of 0 (World Health Organization [WHO]) and an alkaline phosphatase serum level less than 1.25 times the upper limit of normal (N). These patients had a median survival duration greater than 4 years. Intermediate-prognosis patients were characterized by either a WHO performance status < or = 1 or an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of 10 months and a 4-year survival rate of only 15%. The poor-prognosis group had both a WHO performance status > or = 1 and an alkaline phosphatase level > or = 1.25 N. These patients had a median survival duration of only 4 months and none survived beyond 14 months. Treatment strategies for these three groups are discussed. It is suggested that this prognostic model be validated in other patients series.

Interleukin-2-induced thyroid dysfunction is correlated with treatment duration but not with tumor response.

PURPOSE: To analyze the putative relationship between immunotherapy-associated dysthyroidism and the probability of a tumor response. PATIENTS AND METHODS: A total of 89 consecutive patients with advanced cancer were treated with interleukin-2 (IL2)-based immunotherapy in a prospective study. RESULTS: Twenty patients developed thyroid dysfunction. Repeatedly positive tests for thyroid antibodies developed in 28% of the patients. Twenty-two patients achieved a response. There was no relationship between the formation of antibodies and the probability of response. There appeared to be a trend toward a relationship between thyroid dysfunction and response (P = .23). A strong relationship was found between response on the one hand and cumulative dose of IL2 (P = .01) and treatment duration with IL2 (P = .025) on the other. The frequency of thyroid dysfunction was also significantly correlated with treatment duration (P = .001). After adjustment for cumulative dose of IL2 and treatment duration, no relationship between thyroid dysfunction and response remained (P = .99). CONCLUSION: There is no relationship between thyroid dysfunction and the probability of tumor response. Thyroid dysfunction is merely a function of treatment duration and cumulative dose of IL2.

Sequential administration of recombinant human interleukin-2 and dacarbazine in metastatic melanoma: a multicenter phase II study.

Twenty-five assessable patients with metastatic melanoma have been entered in a multicenter phase II study of two induction cycles of human recombinant interleukin-2(IL2), 18 x 10(6) IU/m2/d continuous intravenous (IV) infusion on days 1 to 5 and days 12 to 17. Dacarbazine (DTIC), 850 mg/m2 IV bolus was given on day 26. The cycle was repeated at 5 weeks. Maintenance therapy was scheduled 3 weeks after the completion of induction treatment, consisting of IL2, 18 x 10(6) IU/m2/d for 5 days alternating with DTIC, 850 mg/m2 IV every 3 weeks, for a total of 18 weeks. Six patients responded (24%); two complete and four partial. Stable disease was seen in five patients. None of the six patients with more than two sites of metastases responded. Maximum response was observed in the first 3 months of treatment. Progression-free periods of 6 months and longer were seen in the two complete responders (8 and 17+ months), in two of the four partial responders (7 and 12+ months), and in three of the five patients with stable disease (9+, 15, and 17+ months). Toxicity included fever, skin rash, fatigue, anorexia, and diarrhea in most patients. Two patients had a weight gain of more than 10%. Eight patients needed intensive care for the observation and treatment of a myocardial injury (one patient), ventricular tachycardia (one), hypotension and oliguria (four), and sepsis (two). Sequential treatment with IL2 and DTIC appears to be effective but not clearly better than could be expected of IL2 alone.

Importance of bleomycin in combination chemotherapy for good-prognosis testicular nonseminoma: a randomized study of the European Organization for Research and Treatment of Cancer Genitourinary Tract Cancer Cooperative Group.

PURPOSE: This prospective randomized trial was designed to compare the efficacy of etoposide plus cisplatin (EP) versus bleomycin, etoposide, and cisplatin (BEP) chemotherapy in patients with good-prognosis metastatic nonseminomatous testicular cancer. PATIENTS AND METHODS: Four hundred nineteen patients with good-prognosis nonseminomatous testicular cancer were randomized to receive four cycles of cisplatin 20 mg/m2 on days 1 to 5 plus etoposide 120 mg/m2 on days 1, 3, and 5 with or without bleomycin 30 mg weekly. RESULTS: Of 395 eligible patients, 169 of 195 patients allocated to EP (87%) and 189 of 200 patients allocated to BEP (95%) achieved a complete response with chemotherapy alone or after postchemotherapy surgery. These results are significantly different (P = .0075). After a median follow-up duration of 7.3 years, eight patients (4%) on each treatment arm relapsed. In view of the low number of unfavorable treatment outcomes (11%), no significant differences were detected in time to progression (P = .136) and survival (P = .262). Both the acute and late pulmonary toxicity and neurotoxicity were significantly greater in patients who received BEP, whereas Raynaud's phenomenon occurred exclusively in patients who received BEP (P < .001). Two patients treated with BEP died of bleomycin pulmonary toxicity. CONCLUSION: BEP is the most effective combination regimen in the treatment of disseminated nonseminomatous germ cell cancer. In this particular BEP regimen with etoposide at a dose of 360 mg/m2 per cycle, even in good-prognosis patients, bleomycin cannot be deleted without compromising treatment efficacy, but its use is associated with more toxicity (particularly pulmonary) and efforts to reduce this merit further exploration.

Analysis of cumulative probabilities shows that the efficacy of 5HT3 antagonist prophylaxis is not maintained.

PURPOSE: Several investigators have reported that the efficacy of 5HT3 receptor antagonists is maintained over repeated cycles of chemotherapy. These investigators presented conditional probabilities of protection. Because conditional analyses by definition only include patients with protection in previous cycles, the results are flattered. PATIENTS AND METHODS: We applied a novel statistical approach to investigate whether the efficacy of the 5HT3 receptor antagonist ICS 205-930 (tropisetron) is maintained over repeated cycles of weekly high-dose cisplatin. Overall protection was determined based on cumulative probabilities with the Kaplan-Meier method. Complete protection was calculated with a three state model for transitional probabilities. Eighty-three patients were studied. RESULTS: Over six consecutive cycles, protection against both acute and delayed emesis decreased significantly. The initial complete and overall protection rates against acute emesis of 71% and 95%, respectively, decreased to 43% and 72% in the sixth cycle of chemotherapy. Similarly, the protection rates of 31% and 68% against delayed emesis decreased to 6% and 40%, respectively. CONCLUSION: We conclude that overall and complete long-term protection is more accurately measured by cumulative probabilities than with a method that is based on conditional probabilities. Our statistical approach shows that the efficacy of 5HT3 antagonists is not maintained.

Body-surface area-based dosing does not increase accuracy of predicting cisplatin exposure.

PURPOSE: Most anticancer drugs are dosed based on body-surface area (BSA) to reduce interindividual variability of drug effects. We evaluated the relevance of this concept for cisplatin by analyzing cisplatin pharmacokinetics obtained in prospective studies in a large patient population. PATIENTS AND METHODS: Data were obtained from 268 adult patients (163 males/105 females; median age, 54 years [range, 21 to 74 years]) with advanced solid tumors treated in phase I/II trials with cisplatin monotherapy or combination chemotherapy with etoposide, irinotecan, topotecan, or docetaxel. Cisplatin was administered either weekly (n = 93) or once every 3 weeks (n = 175) at dose levels of 50 to 100 mg/m(2) (3-hour infusion). Analysis of 485 complete courses was based on measurement of total and non-protein-bound cisplatin in plasma by atomic absorption spectrometry. RESULTS: No pharmacokinetic interaction was found between cisplatin and the anticancer drugs used in combination therapies. A linear correlation was observed between area under the curves of unbound and total cisplatin (r = 0.63). The mean plasma clearance of unbound cisplatin (CL(free)) was 57.1 +/- 14.7 L/h (range, 31.0 to 116 L/h), with an interpatient variability of 25.6%. BSA varied between 1.43 and 2.40 m(2) (mean, 1.86 +/- 0.19 m(2)), with an interpatient variability of 10.4%. When CL(free) was corrected for BSA, interindividual variability remained in the same order (23.6 v 25.6%). Only a weak correlation was found between CL(free) and BSA (r = 0.42). Intrapatient variability in CL(free), calculated from 90 patients was 12.1% +/- 7.8% (range, 0.30% to 32.7%). CONCLUSION: In view of the high interpatient variability in CL(free) relative to variation in observed BSA, no rationale for continuing BSA-based dosing was found. We recommend fixed-dosing regimens for cisplatin.

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.

Phase II and pharmacologic study of topotecan administered as a 21-day continuous infusion to patients with colorectal cancer.

PURPOSE: Topotecan is a specific inhibitor of topoisomerase I. Preclinical data have indicated that topoisomerase I inhibitors demonstrate more efficacy and have a greater therapeutic index with prolonged continuous exposure. The feasibility of this concept in humans using a 21-day continuous infusion of topotecan has been reported. We conducted a phase II study of this 21-day continuous topotecan administration schedule in patients with locally advanced, unresectable or metastatic colorectal cancer. PATIENTS AND METHODS: Topotecan, initially applied at a dose of 0.6 mg/m2/d, was administered as a continuous infusion via an ambulatory pump for 21 days repeated every 4 weeks. The starting dose was reduced to 0.5 mg/m2/d, because in five of the first 11 patients, the second course had to be delayed due to prolonged myelosuppression. Forty-two patients entered the study; one patient was ineligible and was excluded from further analyses. RESULTS: The overall response rate was 10%, with one complete and three partial responses. The median response duration was 7 months (range, 4 to 11). With this schedule, the major toxicity was prolonged cumulative myelosuppression, including a marked inhibition of erythropoiesis. A total transfusion of 250 U of erythrocytes was needed to maintain a hemoglobin level greater than 6.0 mmol/L. Other side effects were mild, and included alopecia (47%), periodic nausea (40%)/vomiting (22%), and fatigue (16%). Pharmacokinetic evaluation showed a mean steady-state plasma concentration (Css) of topotecan of 0.62 ng/mL (range, 0.33 to 1.1), with a significant relationship between the Css of topotecan and common cytotoxicity criteria (CTC) grade of leukocytopenia. CONCLUSION: Topotecan administered as a 21-day continuous infusion exerts minor activity as single-agent therapy in patients with metastatic colorectal cancer.