Biomedical subjects

R Mick

Publications and source records attributed to R Mick.

At least 55 records · Page 3Linked to original sources

PubMed1996

Refractory cytopenia with multilineage dysplasia: further characterization of an 'unclassifiable' myelodysplastic syndrome.

Myelodysplastic syndromes (MDS) characterized by multilineage cytopenias and dysplasia but lacking an increase in blasts, with no Auer rods or monocytosis, do not exactly fit any of the categories of the French-American-British (FAB) classification of MDS and are often diagnosed as refractory anemia (RA), refractory anemia with ringed sideroblasts (RARS), or 'unclassifiable' MDS. It has been suggested that these 'unclassifiable' cases form a distinct subset with a clinical behavior more like that of refractory anemia with excess of blasts (RAEB) than that of RA or RARS, but few studies have been undertaken that characterize this group. We compared the clinical, hematologic, morphologic and cytogenetic features of 18 such patients - for whose disease we propose the designation 'refractory cytopenia with multilineage dysplasia' (RCMD) - to those of 42 patients meeting the FAB criteria for RA or RARS (14 patients) and RAEB (28 patients). Our results show that cytopenias in RCMD are more severe than those in RA or RARS, but are similar to those in RAEB. Erythroid hyperplasia and dyserythropoiesis are the main findings in bone marrow specimens of RA or RARS, but the major features in RCMD are multilineage proliferation and dysplasia, which, except for the lack of increased blasts resemble the findings in RAEB. Only 1/14 patients (7%) with RA or RARS had an abnormal karyotype, whereas RCMD resembled RAEB in terms of the frequency (41 vs 50%, respectively) and type of karyotypic lesions. Abnormalities of chromosomes 5 and 7 (excluding del(5q) as an isolated finding) or complex aberrations were seen only in RCMD and RAEB. in RCMD, the median survival was 24 months, with a 4-year survival rate of48 +/- 13%, intermediate between the findings in RA/RARS (107 months and 77 +/- 12%, respectively) and RAEB (18 months and 27 +/- 9%, respectively). Our data indicate that RCMD is a distinct subset of MDS, with an unfavorable clinical outcome. The designation 'refractory cytopenia with multilineage dysplasia' emphasizes the differences between such cases and the primarily dyserythropoietic, indolent subgroups of MDS, such as RA or RARS.

Adult↗

PubMed1996

Bone marrow transplantation for the treatment of haematological disorders in Down's syndrome: toxicity and outcome.

We report 18 patients with Down's syndrome who underwent bone marrow transplantation, and review nine previously published patients. The indications for transplant in the combined group of 27 patients were acute lymphoblastic leukaemia in 14 cases (52%), acute myeloid leukaemia in 11 cases (41%) and aplastic anemia in two cases (7%). Transplants were autologous in five cases (19%) and allogeneic in 22 cases (81%); of the 22 allogeneic transplants, 16 donors were HLA-matched siblings. In all patients the conditioning regimen included total body irradiation of 7.5 Gy or more, and/or contained cyclophosphamide of 120 mg/kg or more. Seven patients (26%) had fatal pulmonary disease including pneumonitis and pulmonary hemorrhage. Five patients (19%) had significant airway problems including three with severe mucositis who required intubation for airway protection, one with severe mucositis with partial airway obstruction that required observation in the intensive care unit but did not require intubation, and one with Candida albicans laryngitis with development of a glottic web. Nineteen patients (70%) survived beyond 100 days post-transplant. There was no clear association between 100-day survival and the use of any particular agent or regimen used for conditioning or graft-versus-host disease prophylaxis, and the majority of patients tolerated high-dose cyclophosphamide, high-dose cytosine arabinoside, high-dose busulfan, total body irradiation, cyclosporin A, and methotrexate. There appeared to be more early deaths in patients who received the combination of cyclophosphamide and total body irradiation, compared with those receiving the combination of busulfan and cyclophosphamide or those receiving the combination of cytosine arabinoside and total body irradiation. Also, the use of methotrexate was associated with a greater number of early deaths, compared with cyclosporin A. At 3 years, life table estimates of freedom from relapse, relapse-free survival and survival were 75%, 44% and 48%, respectively. The estimated cumulative risk of death due to a non-leukaemic cause at 3 years was 39%. The data show that Down syndrome patients can tolerate the commonly used transplant conditioning regimens with acceptable toxicity; however, there is a strong suggestion in the data that the rates of life-threatening and fatal toxicity are higher than would be expected to occur in patients without Down's syndrome. Patients with Down's syndrome may have a predisposition to fatal pulmonary complications and reversible airway problems during the immediate post-transplant period.

Adolescent↗

PubMed1996

Human papilloma virus and p53 in head and neck cancer: clinical correlates and survival.

Recent studies have shown that p53 mutations are frequently found in cancer of the head and neck, whereas others have indicated that human papilloma virus (HPV) infection may be involved. Thus far, no studies have examined both p53 and HPV in the same patient population and correlated the results with clinical characteristics and outcome. The purpose of this study was to examine any interrelationship between p53 and HPV in patients with squamous cell carcinoma (SCC) of the head and neck. We also planned to correlate the experimental findings with clinical characteristics, known risk factors, and treatment outcome to determine whether any prognostic factors could be detected. Archival material from 66 patients with SCC of the head and neck were selected for study based on the availability of tissue from the primary tumors prior to treatment. A data base was constructed containing all clinical parameters at the time of diagnosis and risk factors. Genomic DNA was isolated and amplified using PCR, followed by SSCP analysis and direct genomic sequencing of all variants to detect p53 mutations. Two independent methods were used for HPV detection: (a) PCR amplification using primers homologous to the E6 region of HPV 16, 18, and 33, followed by RFLP analysis; and (b) PCR amplification with HPV L1 consensus primers, followed by triple restriction enzyme digestion. The results were entered into the data base for statistical analysis. Twenty-four percent of patients were found to have p53 mutations, and 18% were positive for HPV infection. Only one patient was positive for both. Tonsilar cancer was strongly correlated with HPV (P = 0.0001) and inversely correlated with p53 (P = 0.03). The only clinical parameter associated with p53 mutation was a trend toward a heavier smoking history. A subset analysis of the patients with tonsilar cancer revealed inverse correlations with smoking (P = 0. 015) and alcohol use (P = 0.05). Also, white patients with SCC of the tonsil were more likely to be HPV positive (P = 0.015). No significant relationships with outcome were detected with either p53 or HPV in the entire population. A subset analysis of patients with stage IV disease revealed that HPV infection was correlated with overall survival. This is the largest study to date to examine both p53 and HPV in patients with SCC of the head and neck. Our results suggest that HPV may be involved in the development of these cancers in patients without traditional risk factors and that HPV-related cancers are more prevalent in the white race.

Adult↗

PubMed1995

BCL6 encodes a sequence-specific DNA-binding protein.

Chromosomal rearrangements of BCL6 are commonly associated with diffuse large-cell lymphomas. We set out to determine the DNA-binding site of a glutathione-S-transferase fusion protein containing the BCL6 zinc finger region by employing cyclic amplification and selection of targets (CASTing). From oligonucleotides containing 16 central random bases, sequences binding to the protein on glutathione-coated beads were repeatedly selected and amplified by polymerase chain reaction (PCR). The binding sites were cloned and sequenced. A consensus, TTTNNNGNNATNCTTT, was obtained. Protein binding studies of double-stranded oligomers containing point mutations within the 3' CTTT confirmed the binding specificity of this part of the consensus. In addition, evidence indicated that some of the base pairs held constant in the oligonucleotides used for CASTing also contributed to binding.

Base Sequence↗

PubMed1995

Optimizing selection of patients for major lung resection.

OBJECTIVES: It is not known whether a normal diffusing capacity for carbon monoxide permits safe lung resection in patients with marginal spirometric values, or whether normal spirometric values negate the adverse effects of a low diffusing capacity. The purposes of this study were (1) to determine the best predictors of morbidity and mortality and (2) to assess whether interactions exist between diffusing capacity and spirometry that help estimate outcome after major lung resection. DESIGN: A retrospective analysis of 376 patients who underwent lung resection was performed. Three hundred three had lung cancer and 73 had other disease. Two hundred eighty-four underwent lobectomy/bilobectomy and 92 had pneumonectomy. We assessed the relationship of 23 preoperative variables to 18 postoperative events classified into categories as pulmonary or cardiac complications, overall morbidity, and operative mortality. RESULTS: The best single predictor of complications was the percent predicted postoperative diffusing capacity. The incidences of pulmonary and cardiac complications, morbidity, and mortality were inversely related to predicted postoperative diffusing capacity percent (p < 0.004 for each). Multivariate logistic regression analyses identified only predicted postoperative diffusing capacity percent and age as significant independent predictors of pulmonary complications, morbidity, and death, and these with prior myocardial infarction predicted cardiac complications. There were no interactions between percent predicted postoperative forced expiratory volume in 1 second and predicted postoperative diffusing capacity percent in estimating risks of complications. CONCLUSION: Predicted postoperative diffusing capacity percent is the strongest single predictor of risk of complications and mortality after lung resection. There is little interrelationship of predicted postoperative diffusing capacity percent and predicted postoperative forced expiratory volume in 1 second, indicating that these values should be assessed independently in estimating operative risk.

Female↗

PubMed1995

Induction chemotherapy followed by concomitant chemoradiotherapy for advanced head and neck cancer: impact on the natural history of the disease.

PURPOSE: To determine survival rates and the pattern of failure in head and neck cancer patients treated with induction chemotherapy, limited surgery and concomitant chemoradiotherapy. PATIENTS AND METHODS: Three cycles of induction chemotherapy with cisplatin, fluorouracil (5-FU), leucovorin, and interferon alfa-2b (PFL-IFN) were followed by optional surgery, and seven or eight cycles of 5-FU, hydroxyurea, and concurrent radiation for 5 days (FHX) for a total radiation dose of 65 to 75 Gy. Surgical resection was performed with the intent to spare organ function. RESULTS: Seventy-one patients were treated at three institutions. Sixty-five patients (91%) had stage IV disease with N2/3 in 46. Thirty-three patients (51%; 95% confidence interval, 39% to 63%) achieved a clinical complete response (CR) to PFL-IFN. Local therapy consisted of surgery in 37 and/or FHX in 55 patients. With a median follow-up duration of 37 months, there have been 20 recurrences (15 local, four distant, and one both local and distant), and 29 deaths, 15 in patients with disease progression and 14 not directly related to the primary tumor. Four patients have developed second malignancies. At 3 years, 69% (+/- 6%) are progression-free and the overall survival rate is 60% (+/- 6%). Toxicity of PFL-IFN included severe or life-threatening mucositis (54%) and myelosuppression (60%). Five patients died of toxicity. During FHX, 70% of patients had grade 3 or 4 mucositis. CONCLUSION: PFL-IFN is highly active, producing clinical CRs in 51% of patients, and, when followed by FHX, resulting in high local and distant control and overall survival rates. Second malignancies and intercurrent medical disease emerge as major risks to long-term survival. In view of the high toxicity and long treatment duration, further modifications of this approach are required.

Adolescent↗

PubMed1995

Perceptions of cancer patients and their physicians involved in phase I trials.

PURPOSE: In an attempt to understand some of the complex issues related to the participation of cancer patients in phase I trials, and the perceptions of patients toward these trials, we conducted a pilot survey study of 30 cancer patients who had given informed consent to participate in a phase I trial at our institution. Concurrently, the oncologists identified by the surveyed patients as responsible for their care were surveyed as well. PATIENTS AND METHODS: Twenty-seven of 30 consecutive patients agreed to and completed the survey. Patients were surveyed before they received any investigational agents. Eighteen oncologists participated in this survey study. RESULTS: Eighty-five percent of patients decided to participate in a phase I trial for reasons of possible therapeutic benefit, 11% because of advice/trust of physicians, and 4% because of family pressures. Ninety-three percent said that they understood all (33%) or most (60%) of the information provided about the trials in which they had decided to participate. Only 33% were able to state the purpose of the trial in which they were participating, with patients able to state the purpose of phase I trials being more educated (P = .01). Surveyed oncologists had wide-ranging beliefs regarding expectations of possible benefits and toxicities for their patients participating in phase I trials. CONCLUSION: Cancer patients who participate in phase I trials are strongly motivated by the hope of therapeutic benefit. Altruistic feelings appear to have a limited and inconsequential role in motivating patients to participate in these trials. Cancer patients who participate in phase I trials appear to have an adequate self-perceived knowledge of the risks of investigational agents. However, only a minority of patients appear to have an adequate understanding of the purpose of phase I trials as dose-escalation/dose-determination studies.

Adult↗

PubMed1995

Concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for anaplastic astrocytoma and glioblastoma multiforme.

The survival rate for patients with malignant gliomas is poor. We describe the results of a prospective study using concomitant chemoradiotherapy, neutron boost, and adjuvant chemotherapy for patients with malignant gliomas. Forty-two patients with anaplastic astrocytoma (AA) and glioblastoma multiforme (GBM) were treated with postoperative photon radiation 45 Gy/25 fraction (fxs) with concomitant continuous intravenous infusion of 5-fluorouracil at 300 mg/m2/day x 5 days and hydroxyurea 0.5 g orally every 12 hr for 6 days for 5 consecutive weeks, followed by a neutron boost of 450 N cGy/6 fxs delivered twice weekly. Adjuvant chemotherapy with procarbazine, CCNU, and vincristine (PCV) was given up to 1 year or until tumor progression. Thirty-four patients (81%) had GBM and 8 patients (19%) had AA. Sixteen patients (38%) were ineligible for the neutron boost because of large tumors or poor performance status and instead received a photon boost with concomitant chemotherapy for a total dose of 60-65 Gy to the tumor. The overall median survival is 68 weeks at a median follow-up of 203 weeks (range 166-302 weeks for the 11 patients remaining alive); 7/8 patients with AA are alive, 2 of these with progressive disease. For AA the median survival is not reached at a median follow-up of 203 weeks (range 166-302 weeks for the 7 patients alive with AA). Time to tumor progression for the 1 dead patient with AA was 35 weeks and the other 2 patients failed at 171 weeks and 179 weeks following treatment. The median survival for the 34 patients with GBM was 62 weeks; 4/34 patients with GBM are alive at 285, 238, 216, and 206 weeks. Multivariate survival analysis in the 34 patients with GBM revealed age and Karnofsky performance status as important prognostic factors. Extent of surgery and neutrons did not affect survival. Concomitant chemoradiotherapy was well tolerated by all patients. The only toxicities observed were mucositis < or = grade II in 3 patients (7%) and mild myelosuppression in 1 patient (2.4%). Adjuvant PCV was well tolerated. Continuous concomitant chemoradiotherapy was well tolerated by all patients with acceptable side effects. The survival rate for the patients with GBM suggests no significant impact on the prognosis for these patients. Patients with AA did well; however, the patient numbers are small.

Adolescent↗

PubMed1995

Quantitative CD34 analysis may be used to guide peripheral blood stem cell harvests.

The duration of neutropenia and thrombocytopenia after high-dose chemotherapy has improved since the introduction of myeloid growth factors and peripheral blood progenitor cells (PBPC), yet there remains a subset of patients who have delayed hematopoietic recovery. Currently, there ar no established, reliable parameters which may be used to guide stem cell harvests. We investigated the utility of measuring harvested CD34 positive cell populations by flow cytometry. From March 1990 to July 1993, 30 women with advanced breast cancer underwent therapy with high-dose cyclophosphamide and thiotepa and stem cell rescue. Patients received either cyclophosphamide (CY) mobilized PBPC or CY/G-CSF mobilized PBPC. The number of harvested CD34+ cell and CFU-GM (colony forming units-granulocyte macrophage) were quantitated for each stem cell produce. There ar complete CD34 data for 21 patients and complete CFU-GM data for 20 patients. There was a significantly delayed neutrophil recovery in those patients reinfused with < 0.75 x 10(6) CD34+ cells/kg body weight (median days 22) compared with patients reinfused with > 0.75 x 10(6)/kg (median days 12, P = 0.0004); a similar trend was seen with platelet recovery (median 135 days vs 18 days, respectively, P = 0.002). With neutrophil recovery, there was no improvement in time to engraftment with a large number of reinfused CD34+ cells, but there was a trend towards shortened platelet recovery when the number of reinfused CD34+ cells exceeded 2.0 x 10(6)/kg (median 15 days) compared with CD34+ < 2.0 x 10(6)/kg (median 75 days, P = 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Antigens, CD↗

PubMed1995

Source of stem cells impacts on hematopoietic recovery after high-dose chemotherapy.

The restoration of hematopoiesis after high-dose chemotherapy may be accelerated by the use of stem cells from the bone marrow (BM) or peripheral blood. Numerous reports utilizing mobilized peripheral blood progenitor cells (PBPC) for stem cell rescue have shown that PBPC are sufficient to restore hematopoiesis, but there are little data comparing the recovery among patients treated with various stem cell sources. We reviewed the clinical outcomes of 69 women at our institution who were treated for locally advanced or metastatic breast cancer with high-dose cyclophosphamide (CY) and thiotepa and autologous stem cell and growth factor support. Of the 43 patients with normal BM, 19 received BM alone and 24 received BM plus G-CSF mobilized PBPC. Of the 26 patients with evidence of metastatic disease in the BM, or evidence of fibrosis and hypocellularity, 15 received CY-mobilized PBPC and 11 received CY/G-CSF-mobilized PBPC. Of the marrow-negative patients, those receiving BM alone had significantly longer (P < 0.001) granulocyte recovery (absolute neutrophil count > 500 x 10(6)/l) and platelet recovery (platelets > 50 x 10(9)/l) compared with BM + G-CSF-mobilized PBPC. They also had significantly longer (P < 0.001) durations of antibiotic and amphotericin usage, increased transfusion requirements and longer hospitalizations. Of the marrow-positive patients, there was a slightly shortened granulocyte recovery, shortened hospital stays and lessened amphotericin usage in the patients who received CY/G-CSF-mobilized PBPC compared with the CY-mobilized patients. Although the number of harvested mononuclear cells differed significantly between the groups, this did not correlate with the time to hematopoietic recovery.(ABSTRACT TRUNCATED AT 250 WORDS)

Adult↗

PubMed1995

Clinical and prognostic significance of chromosomal abnormalities in childhood acute myeloid leukemia de novo.

We report on the chromosomal pattern of 120 patients with childhood AML de novo. One hundred and fifteen patients (96%) had adequate samples for analysis; 98 (85%) of these showed clonal karyotypic abnormalities. They were classified into cytogenetic subgroups which were closely correlated with FAB subtypes: t(8;21) and M2 (n = 9); t(15;17) and M3 (n = 12); inv(16) and M4Eo (n = 9); t(9;11) and M5a (n = 10); t(11q23) other than t(9;11) and M4-M5 (n = 11); and t(1;22) and M7 (n = 4). In patients with -7/del(7q) (n = 6), leukemia was preceded by MDS in half of the cases, although they had diverse FAB subtypes. Thirty-seven patients had miscellaneous abnormalities. Despite a high CR rate, patients with t(8;21) had a very poor survival: only one child was event-free at 3 years from diagnosis. One third of patients with t(15;17) died during induction. Those eight who achieved CR fared well: only two relapsed, and six were event-free survivors. Patients with inv(16) had a high remission rate and a long survival: five children were in CR 20 to 136 months. Both groups with t(9;11) and t(11q23) had a high remission rate: however, outcome was superior for the t(9;11) group when compared to either the t(11q23) group (EFS at 3 years +/- SE, 56 +/- 17% vs. 11 +/- 10%, p = 0.07) or to the remaining patients (p = 0.06). Both -7/del(7q) and t(1;22) groups had low CR rates (50%) and poor survival. Cytogenetic analysis identifies clinically distinct subsets of childhood AML and is useful in tailoring treatment for these patients. Favorable cytogenetic groups (t(15;17), inv(16), and t(9;11)) may do well with current therapy protocols, whereas unfavorable groups (t(11q23), t(8;21), -7/del(7q), and t(1;22)) require more effective therapies.

Child↗

PubMed1995

Certain HLA antigens are associated with specific morphologic and cytogenetic subsets of acute myeloid leukemia.

Although many associations have been found between specific HLA antigens and an increased susceptibility to various diseases, previous attempts to associate class I and II antigens with acute myeloid leukemia (AML) have been inconclusive, probably due in part to the heterogeneity of AML. We subdivided 165 consecutive adults with AML de novo into distinct clinical, morphological, and cytogenetic subsets and then tested for statistically significant associations with specific HLA antigens. Both morphology and cytogenetic pattern identified subsets of patients with important clinical features and different outcomes. Ten statistically significant (P < 0.05) HLA cytogenetic associations were observed: HLA-A11 with t(8;21), A26 with t(15;17), B7 with 11q23 abnormalities, B44 with +8, Cw2 with -20/del(20q), DR3 with t(15;17) and FAB-M3, DR4 with inv(16) and FAB-M4Eo, DQ2 with +8, and DQ6 with +22. HLA-DQ1 had a negative association with -5/del(5q), which was present in 13% of the 165 AML patients overall but in none of the 27 with DQ1. Certain HLA antigens were significantly correlated with more favorable remission rates, remission duration and survival. Possible mechanisms for the association of HLA antigens with particular subtypes of AML include the linkage or co-inheritance of an oncogene, the facilitation of binding of a transforming virus, toxin, or cytokine, or a permissive role involving impaired immune recognition of an emerging neoplasm. Given the heterogeneity of both the HLA system of immune recognition genes and the cytogenetic subtypes of AML, however, larger numbers of patients must be studied to have confidence that biologically important relationships truly exist.

Acute Disease↗

PubMed1995

Pharmacokinetics and pharmacodynamics of oltipraz as a chemopreventive agent.

Oral oltipraz, as a single-dose treatment, was evaluated as a chemopreventive agent in 31 normal subjects. In a subset of subjects, the relationship between plasma oltipraz concentrations and the induction of lymphocyte glutathione (GSH) and glutathione S-transferase (GST) enzyme levels was evaluated. Pharmacokinetic analysis revealed nonlinear disposition of oltipraz with disproportionate 40-fold increase and 9.5-fold decrease in peak plasma concentrations (Cmax) and p.o. clearance, respectively, over the dose range of 100-500 mg. There was no correlation between the oltipraz dose and the absorption rate or the time to reach Cmax. Since oltipraz undergoes extensive metabolism, saturable first-pass elimination could be one of the sources of nonlinearity. Pharmacodynamic evaluation was conducted based on the percentage of elevation of GSH and GST levels over baseline in lymphocytes of subjects receiving 100 mg and 125 mg oltipraz. Induction was observed in both dose groups with a time lag between the maximum concentrations of oltipraz and that of GSH or GST. We also observed a linear correlation between oltipraz Cmax and the corresponding GSH and GST elevations. Subjects with higher Cmax values showed a greater increase over baseline in the GSH and GST levels. Mild toxicities were observed at all dose levels. The most common were flatulence, hunger, fatigue, and headache. These preliminary results indicate that oltipraz may be effective in inducing GSH and GST, an enzyme capable of carcinogen elimination.

Administration, Oral↗

PubMed1994

Physician-determined patient risk of toxic effects: impact on enrollment and decision making in phase I cancer trials.

BACKGROUND: The conventional phase I trial design yields an estimate of the maximum tolerated dose (MTD) of a new drug defined from treatment toxic effects observed in a small heterogeneous cohort of patients. The MTD is specific for those patients treated in the study and may not be reproducible in another patient series, a limitation known as cohort dependency. PURPOSE: We conducted an opinion survey of phase I investigators in an attempt to characterize physician attitudes and clinical practices regarding assessment of risk of toxic effects in patients. METHODS: A physician opinion survey of scaled multiple choice and open-ended questions was distributed to oncologists (faculty and fellows) at National Cancer Institute (NCI)-funded phase I contract institutions. The target sample was narrowed to these specific institutions because of their experience in conducting various phase I trials. Each NCI-funded phase I contractor received an instruction sheet and 25 surveys and envelopes that were made available to oncologists enrolling patients in phase I trials. RESULTS: Of the 75 surveys distributed, 67 (89%) were returned. Most respondents agreed that unexplained variability in toxicity exists in phase I trials. However, opinion varied considerably among five participating institutions (two-sided P = .001). Informal scoring of patients for toxicity risk prior to treatment was a common practice (85% overall), although the prevalence of this practice varied somewhat among the institutions (two-sided P = .01). Physicians' opinions were mixed regarding the practice of becoming increasingly selective in enrolling patients as the MTD was approached, with strong disagreement noted among institutions (two-sided P = .001). Given background on a hypothetical phase I trial, respondents were asked to rank the usefulness of 27 patient factors for predicting the risk of dose-limiting leukopenia. Eight factors were perceived as strongly informative: Eastern Cooperative Oncology Group performance status of 2 or worse, recent weight loss of more than 10%, multiple bone marrow metastases, two or more prior chemotherapy regimens, history of treatment toxic effects, and prior treatment with carboplatin, mitomycin, or nitrosoureas. CONCLUSIONS: Informal assessment of the risk of toxic effects in a patient was found to be common practice among oncologists who enroll patients on phase I trials, and there was strong agreement on the usefulness of several key patient factors for such assessments. Interestingly, interinstitutional variation in opinions and practices were noted, specifically regarding patient-selection bias. Follow-up studies are required to establish if physician-determined assessments of patient risk are consistent and accurate.

Adult↗

PubMed1994

Prognostic factors for survival in patients treated in phase I clinical trials.

BACKGROUND: Patients with advanced or metastatic cancer treated in Phase I clinical trials are considered to have a poor prognosis. Survival from first treatment in a Phase I trial was determined for 349 patients. Univariate and multivariate survival analyses were performed to determine whether potential prognostic factors and distinct risk groups could be identified. METHODS: Patients were identified retrospectively from a large data base of patients with advanced or metastatic cancer treated in Phase I clinical trials at the University of Chicago between February 1987 and October 1991. RESULTS: With a median follow-up of 29 months, 10% of patients were alive at the time of analysis. Twenty-nine percent were alive 1 year after the initiation of Phase I chemotherapy, and the median survival from first treatment in a Phase I study was 6.5 months. Multivariate analysis indicated that a better pretreatment performance status, a higher pretreatment serum albumin concentration, a lower pretreatment platelet count, no prior cisplatin chemotherapy, and a genitourinary or gynecologic cancer diagnosis were predictive of better survival. Three risk groups incorporating these five variables were identified, with median survivals of 12.7, 7.4, and 3.5 months for the good, intermediate, and poor risk groups, respectively. CONCLUSION: Patients treated in Phase I clinical trials have a median survival of 6.5 months, even though some patients have been treated at early (subtoxic and potentially subtherapeutic) dose levels. The results of this study may allow the identification of patients who are likely to survive long enough to contribute information on acute and cumulative drug-related toxicities and, possibly, tumor response.

Adult↗

PubMed1994

Metabolic fate of irinotecan in humans: correlation of glucuronidation with diarrhea.

Irinotecan (7-ethyl-10-[4-(1-piperidino)-1-piperidino]carbonyloxy-camptotheci n (CPT-11) is hydrolyzed by the enzyme carboxyl esterase to 7-ethyl-10-hydroxycamptothecin (SN-38), which further undergoes glucuronic acid conjugation to form the corresponding SN-38 glucuronide (SN-38G). SN-38 is believed to be the cause of treatment-related diarrhea, a dose-limiting toxicity of CPT-11 observed in phase I clinical trials. This study investigated the effect of glucuronidation on the concentrations of SN-38 following CPT-11 infusion in 21 patients undergoing a phase I trial. To assess the relationship between gastrointestinal toxicity and pharmacokinetics of CPT-11 and its metabolites, we defined a "biliary index" of SN-38 which was the product of the relative area ratio of SN-38 to SN-38G and the total CPT-11 area under the plasma concentration-time curve. Nine patients with grade 3-4 diarrhea had higher biliary indexes than 12 patients with grade 0-2 diarrhea (median 2228 versus 5499, P = 0.0004). The relatively higher index values, suggestive of higher biliary concentrations of SN-38, were possibly due to low glucuronidation rates. Hence, modulation of glucuronidation may be effective in increasing the therapeutic index of CPT-11.

Antineoplastic Agents, Phytogenic↗

PubMed1994

Increased incidence of second neoplasms in patients treated with interferon alpha 2b for hairy cell leukemia: a clinicopathologic assessment.

We report that there is an unexpectedly high incidence of second neoplasms in patients after treatment of hairy cell leukemia (HCL) with interferon alpha 2b (IFN). In a cohort of 69 patients with HCL entered in a protocol using IFN as the primary treatment, and followed thereafter for a median of 91 months (range, 0.2 to 109 months), 13 patients (19%) developed a second neoplasm. Six neoplasms were of hematopoietic origin, whereas the remaining seven were adenocarcinomas. The expected number of second tumors in this cohort is three (based on calculations from the National Cancer Institute's SEER data), so the excess frequency (observed:expected) is 4.33. However, the excess frequency is even greater for the hematopoietic neoplasms; the expected frequency is 0.15, whereas six hematopoietic tumors occurred, for an observed:expected ratio of 40. In general, the second neoplasms have behaved aggressively, and the median survival after diagnosis of the second neoplasm was only 8.8 months. Although we cannot entirely exclude the possibility that IFN therapy has some direct oncogenic effect, we suspect that increased frequency of second tumors is related to prolonged survival of patients who are immunocompromised because of HCL and thus prone to develop second tumors. If so, the frequency of second neoplasms in patients with HCL may be even greater in the future with continued improvements in therapy.

Adult↗

PubMed1994

Time-dose relationship for local tumor control following alternate week concomitant radiation and chemotherapy of advanced head and neck cancer.

PURPOSE: To analyze the time-dose relationship for local control of disease in patients with advanced head and neck neoplasms enrolled in two sequential Phase I dose escalation studies in which concomitant chemotherapy and radiotherapy were delivered on an alternate week schedule (i.e., 1 week of concomitant therapy alternated with 1 week of rest). METHODS AND MATERIALS: From 1986-1988, 65 patients were enrolled in two Phase I clinical trials. In trial one, 5-fluorouracil and hydroxyurea were administered concomitantly with radiation on an alternate week schedule (39 pts). In trial two, cisplatin was added to 5-fluorouracil and hydroxyurea (26 pts). Fifty-seven patients were evaluable for local control, including 26 patients who had failed prior local therapy and were retreated (group A), and 31 patients who had received no prior local therapy (group B). The median dose of RT and the median duration of therapy were 59.7 Gy and 12 weeks for group A, and 70.2 Gy and 14 weeks for group B, respectively. The biological effective dose of radiation therapy (RT) was calculated using the equation based on the linear quadratic model as proposed by J. Fowler. Univariate and multivariate logistic regression analyses were performed to evaluate prognostic factors for local control. RESULTS: Six of 26 patients in group A and 30 of 31 patients in group B had local control of disease. The 2-year Kaplan-Meier local failure rates were 84% for group A and 4% for group B, respectively. Despite the doubling of treatment duration compared to conventional daily radiotherapy and the low biological equivalent dose calculated (median biological equivalent dose for patients with local control of disease were 50.3 Gy and 48.8 Gy in groups A and B, respectively), local control was achieved in 5/17 patients in group A and 30/31 patients in group B who received RT dose of 59.4 Gy or higher. In multivariate logistic regression analysis, the only significant predictor for local control of disease was RT dose (p = 0.004). Treatment duration, chemotherapy dose intensities, age, and performance status were not significant variables. Decreasing the RT dose by 10 Gy would increase the rate of local failure by 24%. CONCLUSION: Our data suggest that prolongation of treatment duration to twice the normal duration of conventional once-a-day radiotherapy does not result in loss of local control when aggressive cell-cycle specific chemotherapy is given concomitantly with radiotherapy. The usual time-dose relationship based on RT alone does not appear to be applicable when concomitant chemotherapy is added. The clinical significance of biological equivalent dose calculation based on radiotherapy alone is unclear when chemotherapy is given with radiation.

Adult↗