Biomedical subjects

S Piantadosi

Publications and source records attributed to S Piantadosi.

At least 19 recordsLinked to original sources

PubMed1999

Nuclear morphometry adds significant prognostic information to stage and grade for renal cell carcinoma.

OBJECTIVES: Identification of patients with a high probability of recurrence after nephrectomy for renal cell carcinoma (RCC) is required for adjuvant studies of new therapies. Nuclear morphometry predicts prognosis for prostate, bladder, and Wilms' tumors and in RCC according to previous small pilot studies. METHODS: To validate this finding, we studied an additional 101 patients who underwent nephrectomy for Stage pT1 to pT3 RCC at our institution from 1977 to 1993 for whom data regarding recurrence or disease-free survival of greater than 60 months were available. Patient records and pathology specimens were reviewed. Of the 101 patients, 66 (65%) did not experience recurrence with greater than 60 months of follow-up, and 35 (35%) had RCC recurrence with a median time to recurrence of 17 months. Nuclear shape descriptors were tested as predictors of disease recurrence after accounting for stage and grade in proportional hazards regression models. RESULTS: Range of ellipticity (hazards ratio 3.39, P = 0.014) was confirmed to be a significant predictor of recurrence. A prognostic model using stage, grade, and range of ellipticity identified three distinct groups: low, moderate, and high recurrence risk groups, with recurrence rates of 4%, 37%, and 63%, respectively, at 5 years of follow-up. Morphometry significantly (P = 0.018) improved prognostication on the basis of stage and grade alone in this multivariate model. CONCLUSIONS: Nuclear morphometry is valid and accurate in predicting relapse in early-stage RCC. The model can select patients with RCC for adjuvant therapies.

Carcinoma, Renal Cell↗

PubMed1998

DNA content and other factors associated with ten-year survival after resection of pancreatic carcinoma.

BACKGROUND AND OBJECTIVES: The 5-year survival rates after resection of pancreatic carcinoma have recently increased and are predicted by tumor size, DNA content, and lymph node metastases at the time of resection. However, whether the 10-year survival rates have also increased and are similarly predicted by these factors is not known. METHODS: The influence of preoperative imaging tests, alcohol consumption, cigarette smoking, K-ras mutations, anatomic location, details of surgical resection, pathologic findings, and tumor DNA content on survival was tested for 96 patients after a successful resection of a pancreatic carcinoma with 17 patients being followed for more than 5 years. RESULTS: The 5- and 10-year patient survival rates were 18% and 3%, respectively. Univariate and multivariable analyses showed that tumor DNA content, pathologic tumor size, and lymph node metastases were the strongest prognostic indicators for long-term patient survival, although the importance of tumor size may diminish 2 or more years after resection. Surprisingly, the 11 patients with diploid carcinomas > or = 4 cm had an estimated 10-year survival rate of 36%. CONCLUSION: These results show that the 10-year survival rate for pancreatic carcinoma remains very low, although the subset of patients with biologically favorable tumors has a prolonged survival and possible cure after resection.

Adenocarcinoma↗

PubMed1998

Practical implementation of a modified continual reassessment method for dose-finding trials.

PURPOSE: We describe a practical, reliable, efficient dose-finding design for cytotoxic drugs applied in a multi-institutional setting. METHODS: The continual reassessment method (CRM) was modified for use in phase I trials conducted through the New Approaches to Brain Tumor Therapy (NABTT) Consortium. Our implementation of the CRM uses (1) a simple dose-toxicity model to guide data interpolation, (2) groups of three patients to minimize calculations and stabilize estimates, (3) investigators' clinical knowledge or opinion in the form of data to make the process easier to understand, and (4) a flexible computer program and interface to facilitate calculations. RESULTS: The modified CRM was used in two dose-finding trials of 9-aminocamptothecin in patients with newly diagnosed and recurrent glioblastoma who were taking anticonvulsant medication. The CRM located the maximum tolerated dose (MTD) efficiently in both trials. Compared to conventional designs, the CRM required slightly more than half the number of patients expected, did not greatly overshoot the MTD (i.e. no patients were treated at dangerously high doses), and did not underestimate the MTD. CONCLUSIONS: Our experience demonstrates the feasibility of implementing this design in multi-institutional trials and the possibility of performing dose-finding studies that require fewer patients than conventional methods.

Antineoplastic Agents↗

PubMed1998

Increased 9-aminocamptothecin dose requirements in patients on anticonvulsants. NABTT CNS Consortium. The New Approaches to Brain Tumor Therapy.

BACKGROUND: High grade astrocytomas remain uniformly fatal despite aggressive surgery and radiotherapy. As existing chemotherapeutic agents are of limited benefit, clinical trials are underway to screen new drugs, such as 9-aminocamptothecin (9-AC), for activity in high grade astrocytomas. PURPOSE: This study was designed to estimate the efficacy of 9-AC in patients with newly diagnosed glioblastoma multiforme and recurrent high grade astrocytomas. The planned dose of 9-AC for this trial was 850 microg/m2 per 24 h as a 72-h continuous intravenous infusion every 2 weeks. This was the maximum tolerated dose (MTD) on this schedule in multiple phase I studies in patients with systemic malignancies. However, we found this dose subtherapeutic in our patient population. As a result, the purpose of the study was altered to determine the MTD. METHODS: A group of 32 patients were studied using 850 microg/m2 per 24 h with a provision to escalate to 1000 microg/m2 per 24 h if the first three cycles of 9-AC were without significant hematologic toxicity. Once it was determined that myelosuppression did not occur in patients on anticonvulsants, dose escalations were initiated using the continual reassessment method. Dose escalations were conducted independently in newly diagnosed and recurrent patients and in those taking and not taking hepatic enzyme-inducing anticonvulsants. Pharmacologic studies were conducted during the first cycle of 9-AC. Toxicity was determined using the NCI common toxicity criteria and efficacy was assessed using serial volumetric brain scans. RESULTS: 9-AC was administered to 59 patients, 31 with newly diagnosed glioblastoma multiforme and 28 with recurrent high grade astrocytomas. No grade III-IV myelosuppression was noted in the 29 patients (128 cycles) on phenytoin, carbamazepine, phenobarbital, and/ or valproic acid who received 850 microg/m2 per 24 h. In contrast, two of three patients (five cycles) who were not taking anticonvulsants developed grade IV myelosuppression. Steady-state total 9-AC plasma levels were lower in patients on anticonvulsants (median 25.3 nM) than in patients who were not taking anticonvulsants (median 76.5 nM). Dose escalations performed in 27 additional patients determined the MTD in patients taking anticonvulsants to be 1776 microg/m2 per 24 h for patients with newly diagnosed tumors and 1611 microg/m2 per 24 h for patients with recurrent disease. CONCLUSIONS: We describe a new and unexpected drug interaction between 9-AC and anticonvulsants. This is similar to recent findings with paclitaxel, and suggests that higher than "usual" doses of some chemotherapeutic agents are required in patients on anticonvulsants. Prospectively defined dose escalations and pharmacologic studies are essential for the careful evaluation of new chemotherapeutic agents in patients with brain tumors.

Adolescent↗

PubMed1998

CD34+ stem cell augmentation of elutriated allogeneic bone marrow grafts: results of a phase II clinical trial of engraftment and graft-versus-host disease prophylaxis in high-risk hematologic malignancies.

Although T cell depletion of allografts used in BMT has reduced GVHD, it has been associated with inferior engraftment and an increased risk of relapse. We have found that T cell depletion by counterflow centrifugal elutriation (CCE) also results in depletion of CD34+ stem cells. In order to determine if the discarded CD34+ cells would improve engraftment, we undertook a phase II trial of allogeneic BMT in which 110 patients (median age 43) with a variety of hematologic malignancies received CD34+ stem cell augmented, elutriated marrow grafts. The T cell-depleted grafts were tightly controlled and contained a mean of 4.3 x 10(7) mononuclear cells/kg, 3.3 x 10(6) CD34+ cells/kg, 1.5 x 10(5) CFU-GM/kg and 5.5 x 10(5) CD3+ T cells/kg. Median time to engraftment of granulocytes (>500/microl) was 16 days and of platelets (>50000/microl) was 25 days, comparable to that seen with unmanipulated marrow. No mixed hematopoietic chimerism was observed that was not associated with disease relapse. The four patients (3.6%) who failed to engraft were all at high risk because of prior donor transfusions or underlying marrow disorders. The incidence of GVHD was dependent on the duration of cyclosporin A (CsA) immunosuppression. In patients who received CsA for > or = 80 days, the incidence of clinically significant acute GVHD (>stage 1) and extensive, chronic GVHD was 5% and 11%, respectively. Peritransplant (< or = 100 day post-BMT) mortality for this group of patients was 15%. Event-free survival in selected subsets of patients compared favorably to previous studies in which patients received unmanipulated marrow allografts.

Adolescent↗

PubMed1998

A randomized controlled trial comparing the cuffed oropharyngeal airway and the laryngeal mask airway in spontaneously breathing anesthetized adults.

BACKGROUND: The cuffed oropharyngeal airway (COPA), a modified Guedel airway, was compared with the laryngeal mask airway (LMA) during spontaneous breathing anesthesia. Specifically examined were ease of use, physiologic tolerance, and the frequency of problems. METHODS: Adult patients consented to random (2:1) assignment to either COPA (n = 302) or LMA (n = 151) for airway management during anesthesia with propofol, nitrous oxide, and oxygen. RESULTS: Ease of insertion was similar, but the first-time successful insertion rate was higher with the LMA (COPA, 81% compared with LMA, 89%; P = 0.05). More brief manipulations (head tilt, chin lift, jaw thrust) were reported in the COPA group (average total number of manipulations: COPA, 1.1 +/- 1.6 compared with LMA, 0.1 +/- 0.2; P < 0.001). Continuous airway support was used more frequently in the COPA group (COPA, 30% compared with LMA, 0%; P < 0.0005). The incidences of aspiration, regurgitation, laryngospasm, wheezing, succinylcholine administration, oxygen saturation (SpO2) < 92%, failed use, and minor intraoperative problems were similar. When the airways were removed, blood was detected on the COPA less frequently than on the LMA (COPA, 5.8% compared with LMA, 15.3%; P = 0.001). The incidence of early and late sore throat was greater with the LMA (early: COPA, 4.7% compared with LMA, 21.9% [P = 0.001]; late: COPA, 8.4% compared with LMA, 16.1%; P = 0.01). The LMA did better than the COPA when anesthetists analyzed the technical aspects of the two devices. CONCLUSIONS: Although the COPA and LMA are equivalent devices in terms of physiologic alterations and overall clinical problems associated with their use, the LMA was associated with a higher first-time insertion rate and fewer manipulations, suggesting that it is easier to use. The COPA was associated with less blood on the device and fewer sore throats, suggesting it may cause less pharyngeal trauma. Ultimately, both devices were similar in establishing a safe and effective airway for spontaneously breathing anesthetized adults.

Adult↗

PubMed1998

Polymerase chain reaction-based microsatellite polymorphism analysis of follicular and Hürthle cell neoplasms of the thyroid.

Follicular and Hürthle cell carcinomas of the thyroid cannot be differentiated from adenomas by either preoperative fine needle aspiration or intraoperative frozen section examination, and yet there exist potentially significant differences in the recommended surgical management. We examined, by PCR-based microsatellite polymorphism analysis, DNA obtained from 83 thyroid neoplasms [22 follicular adenomas, 29 follicular carcinomas, 20 Hürthle cell adenomas (HA), and 12 Hürthle cell carcinomas (HC)] to determine whether a pattern of allelic alteration exists that could help distinguish benign from malignant lesions. Alterations were found in only 7.5% of informative PCR reactions from follicular neoplasms, whereas they were found in 23.3% of reactions from Hürthle cell neoplasms. Although there were no significant differences between follicular adenoma and follicular carcinoma, HC demonstrated a significantly greater percentage of allelic alteration than HA on chromosomal arms 1q (P < 0.001) and 2p (P < 0.05) by Fisher's exact test. The documentation of an alteration on either 1q or 2p was 100% sensitive and 65% specific in the detection of HC (P < 0.0005, by McNemar's test). In conclusion, PCR-based microsatellite polymorphism analysis may be a useful technique in distinguishing HC from HA. Potentially, the application of this technique to aspirated material may allow this distinction preoperatively and thus facilitate more optimal surgical management. Consistent regions of allelic alteration may also indicate the locations of critical genes, such as tumor suppressor genes or oncogenes, that are important in the progression from adenoma to carcinoma. Finally, this study demonstrates that Hürthle cell neoplasms, now considered variants of follicular neoplasms, differ significantly from follicular neoplasms on a molecular level.

Adenocarcinoma↗

PubMed1998

Immunomodulatory properties of antineoplastic drugs administered in conjunction with GM-CSF-secreting cancer cell vaccines.

Cancer cells genetically modified to secrete immunoregulatory cytokines offer great promise for human cancer treatment as tumor vaccines. However, in preclinical animal studies, large established cancer burdens have appeared difficult to eradicate with such vaccines. For example, lethally-irradiated GM-CSF-secreting CT26 colon carcinoma cell vaccine therapy tends to cure only animals bearing 1 x 10(5) wild-type CT26 cells or less. For many human cancers, antineoplastic chemotherapy can often significantly reduce systemic cancer burdens. Unfortunately, for most advanced metastatic solid organ cancers, such as cancers of the breast, colon, and prostate, antineoplastic drug treatments generally fail to effect cancer cures. Treatment regimens combining genetically-modified cancer cell vaccine therapy and antineoplastic chemotherapy have the potential to increase advanced cancer cure rates if antineoplastic drugs and drug combinations that do not inhibit vaccine-induced immune responses can be identified. To assess the potential immunomodulatory properties of commonly-used antineoplastic drugs that might be used in combination with cancer vaccine treatments, we studied the effects of the drugs on antitumor immune responses manifest by animals receiving lethally-irradiated GM-CSF-secreting CT26 cell vaccines. Immunomodulatory properties of the antineoplastic drugs were evaluated i) by monitoring drug effects on the generation of tumor-specific CD8+ cytotoxic T-lymphocytes (CTLs) in response to GM-CSF-secreting CT26 vaccine administration, ii) by determining drug effects on the resistance of vaccinated animals to subsequent challenge with lethal inoculac of CT26 cells, and iii) by evaluating combination drug and vaccine treatment efficacy against established CT26 tumors. Using this approach, doxorubicin was found to possess apparent immunostimulatory activities, depending on the dose and schedule of administration, while cyclophosphamide appeared immunosuppressive. The different immunomodulatory properties of doxorubicin and cyclophosphamide may be clinically relevant: combination doxorubicin and vaccine treatment of established CT26 cancers increased cure rates over that achieved with either agent alone, while combination cyclophosphamide and vaccine treatment of animals carrying CT26 tumors was no better in curing the animals than drug treatment alone.

Adjuvants, Immunologic↗

PubMed1997

Bioactivity of autologous irradiated renal cell carcinoma vaccines generated by ex vivo granulocyte-macrophage colony-stimulating factor gene transfer.

Granulocyte-macrophage colony-stimulating factor (GM-CSF) gene-transduced, irradiated tumor vaccines induce potent, T-cell-mediated antitumor immune responses in preclinical models. We report the initial results of a Phase I trial evaluating this strategy for safety and the induction of immune responses in patients with metastatic renal cell carcinoma (RCC). Patients were treated in a randomized, double-blind dose-escalation study with equivalent doses of autologous, irradiated RCC vaccine cells with or without ex vivo human GM-CSF gene transfer. The replication-defective retroviral vector MFG was used for GM-CSF gene transfer. No dose-limiting toxicities were encountered in 16 fully evaluable patients. GM-CSF gene-transduced vaccines were equivalent in toxicity to nontransduced vaccines up to the feasible limits of autologous tumor vaccine yield. No evidence of autoimmune disease was observed. Biopsies of intradermal sites of injection with GM-CSF gene-transduced vaccines contained distinctive macrophage, dendritic cell, eosinophil, neutrophil, and T-cell infiltrates similar to those observed in preclinical models of efficacy. Histological analysis of delayed-type hypersensitivity responses in patients vaccinated with GM-CSF-transduced vaccines demonstrated an intense eosinophil infiltrate that was not observed in patients who received nontransduced vaccines. An objective partial response was observed in a patient treated with GM-CSF gene-transduced vaccine who displayed the largest delayed-type hypersensitivity conversion. No replication-competent retrovirus was detected in vaccinated patients. This Phase I study demonstrated the feasibility, safety, and bioactivity of an autologous GM-CSF gene-transduced tumor vaccine for RCC patients.

Adult↗

PubMed1997

Optimizing interstitial delivery of BCNU from controlled release polymers for the treatment of brain tumors.

Two approaches for improving the interstitial administration of carmustine (BCNU) using 3.8% loaded poly(carboxyphenoxypropane-sebacic acid), an implantable biodegradable anhydride which significantly prolongs survival in patients with recurrent malignant gliomas, were evaluated. First, increasing the ratio of carboxyphenoxypropane (CPP) to sebacic acid (SA) in the polymer increases its hydrolytic stability, thus prolonging its half-life in vivo, and extending the period of drug release. A second approach is to increase the dose of drug loaded into the polymer. This study evaluated the relative merits of these two approaches by comparing release kinetics, safety, and efficacy of escalating BCNU does in polymers with 20:80 and 50:50 ratios of CPP to SA. At the highest dose tested, the 50:50 polymer released BCNU 2.5 times as long in vitro as the 20:80 polymer. Both formulations were nontoxic in rat brains for all BCNU doses tested except 32%. The 20:80 and 50:50 polymers were equally effective in the rat intracranial 9L-glioma model. A dose-response relationship for BCNU was observed (hazard ratio 0.8354 for each mg/kg increase, P < 0.001). The two highest loading doses of BCNU improved survival 40-fold (P < 0.001). The 20% BCNU-loaded 20:80 polymer achieved the best balance of toxicity and antitumor efficacy, yielding a 75% long-term survival rate. Further evaluation of this polymer in monkeys suggests that it might be used with acceptable toxicity. This study establishes that a dose-escalation strategy for improving BCNU controlled-release polymers is more effective than adjusting the ratio of CPP to SA to prolong drug release.

Animals↗

PubMed1997

Correlation of prostate needle biopsy and radical prostatectomy Gleason grade in academic and community settings.

Prior studies have not analyzed grading patterns and accuracy in nonacademic sites and have not analyzed reasons for discrepant grades. We analyzed 499 radical prostatectomy (RP) specimens at The Johns Hopkins Hospital (JHH) from 1994 and compared them with the corresponding JHH needle biopsy Gleason grade and, when available (n = 390), to the outside institution (non-JHH) Gleason biopsy grade. For JHH, there was exact agreement between biopsy and RP in 58% and agreement to within one digit in 93% of cases, compared with 34% and 67%, respectively, for non-JHH. Combining cases into more meaningful groups (Gleason 2-4, 5-6, 7, and 8-10), there was 66% exact correlation between the biopsy and RP for JHH as compared with 45% for non-JHH. Non-JHH undergraded biopsy results more than JHH, with 22.3% and 1.2% Gleason score 2-4, respectively. None of the cases with a Gleason score of 2-4 on biopsy from JHH or non-JHH were Gleason score 2-4 on RP. Fifty-five percent of the tumors with non-JHH needle biopsy results graded Gleason 2-4 had either capsular penetration, seminal vesicle, or lymph node involvement. All of the tumors with needle Gleason score 2-4 at JHH were organ confined. The JHH needle biopsy grade correlated better with pathologic stage than did non-JHH (R = 0.27 JHH vs. R = 0.12 non-JHH). Extent of cancer in the biopsy sample was not a factor in the accuracy of predicting RP grade or stage. Eighty-two cases evaluated at JHH were signed out by a genitourinary pathologist; the grading of the biopsy samples by other JHH pathologists was just as accurate. Gleason score of > or = 7 on the biopsy sample predicted a Gleason score of > or = 7 in the RP 87.5% of the time. A Gleason score of < 7 predicted a Gleason score of < 7 only 63.9% of the time. Discordant grades in some cases reflected patterns of cancer on needle biopsy that were borderline between two different Gleason scores. Sampling was the major source of discrepancy and was often due to the high-grade component in the RP not being present in the biopsy results or due to a component of cancer on the needle reflecting such a small percentage of the pattern seen on RP that this pattern was not included in the final RP Gleason score.

Academic Medical Centers↗

PubMed1997

A new subarachnoid hemorrhage grading system based on the Glasgow Coma Scale: a comparison with the Hunt and Hess and World Federation of Neurological Surgeons Scales in a clinical series.

OBJECTIVE: Although the Hunt and Hess Scale (HHS) and World Federation of Neurological Surgeons Scale (WFNSS) are the most widely used subarachnoid hemorrhage (SAH) grading systems, neither system has achieved universal acceptance. We propose a simplified grading system based entirely on the Glasgow Coma Scale (GCS), which compresses the 15-point GCS into five grades that are comparable with those of the HHS and WFNSS. We refer to this system as the GCS grading system and present a direct comparison with the HHS and WFNSS for predictive value regarding patient outcome and interrater reliability. METHODS: We reviewed 291 consecutive patients with aneurysms treated at our institution between January 1992 and January 1996 and compared the admission grades from the GCS, WFNSS, and HHS with outcome measures at discharge from hospitalization. The Glasgow Outcome score was used as the major outcome measure to evaluate the predictive value of the three scales. Mortality and length of stay (LOS) were also evaluated as outcome measures. The predictive value of each scale was tested with an ordinal logistic regression model for Glasgow Outcome score, a logistic regression model for mortality data, and a linear regression model for LOS. RESULTS: Using the logistic regression model, the GCS was the best predictor of discharge Glasgow Outcome score, with an odds ratio of 2.585 (P = 0.0001), compared with 2.311 (P = 0.0001) for the WFNSS and 2.262 (P = 0.0001) for the HHS. Using mortality data in the logistic model, the HHS was the best predictor, with an odds ratio of 3.391 (P = 0.0001), compared with 2.859 (P = 0.0001) for the GCS and 2.560 (P = 0.0001) for the WFNSS. Each of the three scales had a high predictive value for LOS, using a linear model. We discuss, however, the problematic nature of LOS as an outcome measure for SAH. Interrater reliability for each scale was evaluated using kappa statistics, based on 15 additional patients evaluated prospectively, and showed that the GCS grade also had the greatest interrater reliability, with a kappa of 0.46 (P = 0.0002), compared with 0.41 (P = 0.0005) for the HHS and 0.27 (P = 0.027) for the WFNSS. CONCLUSION: We conclude that the GCS grade has equal or greater predictive value regarding outcome after SAH than do the currently used grading systems and that it has greater reproducibility across observers. Broader familiarity with the GCS among medical and paramedical personnel may further enhance the usefulness of the GCS grade over the HHS and WFNSS in providing a standardized, universally accepted grading system for SAH.

Aneurysm, Ruptured↗

PubMed1997

APC gene mutations and extraintestinal phenotype of familial adenomatous polyposis.

BACKGROUND: Familial adenomatous polyposis (FAP) is caused by germline mutation of the adenomatous polyposis coli (APC) gene on chromosome 5q. AIMS: This study assessed genotype-phenotype correlations for extraintestinal lesions in FAP. METHODS: Mutations of the APC gene were compared with the occurrence of seven extraintestinal manifestations in 475 FAP patients from 51 families. The frequency of manifestations was adjusted for different ages of patients using person years of exposure. In pedigrees without identified APC gene mutation, analysis of linkage to chromosome 5q and/or assessment of neoplasms for replication errors characteristic of mutation in mismatch repair genes were performed. RESULTS: FAP patients from the 42 families (82%) with identified mutations of the APC gene had more frequent expression of extraintestinal manifestations than affected individuals without identified mutations (risk ratio 1.2-4.0; significant difference for cutaneous cysts). The presence of a cutaneous cyst or extraintestinal cancer significantly increased the likelihood of detection of a mutation in the APC gene (94% and 92% respectively; p < 0.05). In patients without identified APC gene mutation, linkage to the APC gene was found in one large family (lod = 5.1, theta 0.01), and replication error phenotype was absent in all 24 neoplasms from 16 members of these nine pedigrees. Expression of pigmented ocular fundus lesions was strongly associated with mutations in codons 541-1309, but no other extraintestinal manifestations were related to mutation position. Multiplicity of extraintestinal manifestations was high with mutation in codons 1465, 1546, and 2621. CONCLUSIONS: Patients with the colorectal phenotype of FAP but no extraintestinal manifestations may have non-truncating mutations of the APC gene or mutation in a gene other than APC or mismatch repair genes. The site of APC gene mutation is associated with pigmented ocular fundus lesions (codons 542-1309) and predisposition to multiplicity of extraintestinal manifestations (codons 1465, 1546, and 2621).

Adenomatous Polyposis Coli↗

PubMed1997

Phase II study of continuous infusion carmustine and cisplatin followed by cranial irradiation in adults with newly diagnosed high-grade astrocytoma.

PURPOSE: To evaluate the activity and toxicity of carmustine (BCNU) and cisplatin administered as a 72-hour continuous intravenous infusion before radiation in adults with newly diagnosed high-grade astrocytomas. PATIENTS AND METHODS: Fifty-two patients with a Karnofsky performance status greater than 60 and no prior antineoplastic therapy entered this protocol. The median age of the patients was 55 years. Eighty-eight percent had glioblastoma multiforme and 12% had anaplastic astrocytomas. BCNU (40 mg/m2/d) and cisplatin (40 mg/m2/d) were administered concurrently as a 72-hour infusion every 3 to 4 weeks. Radiation was begun 4 weeks after the third cycle of chemotherapy or earlier for progressive disease. Responses required a > or = 50% reduction in contrast-enhancing volume. RESULTS: Forty patients (77%) completed three chemotherapy infusions, five (10%) received two infusions, and seven (13%) received only one. Fifty-one patients completed radiation. Seventeen (42%) patients with measurable disease had a partial response (PR) to chemotherapy, 23 (53%) had stable disease (SD), and two (4%) had progressive disease (PD) on chemotherapy. The median survival time for all patients was 13 months. Survival rates at 1, 2, 3, and 5 years were 62%, 19%, 12%, and 5%, respectively. Grade III to IV leukopenia occurred in 32% of patients; 63% received platelet transfusions and 58% required RBCs. Neutropenic fevers were rare and no intracranial hemorrhages or treatment-related deaths were noted. Nausea, vomiting, peripheral neuropathy, hearing loss, and thromboembolic events were relatively common. CONCLUSION: This chemotherapy regimen appears to have significant activity and may prolong survival in adults with newly diagnosed high-grade astrocytoma.

Adult↗

PubMed1997

Preirradiation paclitaxel in glioblastoma multiforme: efficacy, pharmacology, and drug interactions. New Approaches to Brain Tumor Therapy Central Nervous System Consortium.

PURPOSE: The purpose of this study was to determine the response rate of paclitaxel administered at maximal tolerated doses (MTD) in patients with newly diagnosed glioblastoma multiform. PATIENTS AND METHODS: All patients in this multicenter study were 45 years or older and had measurable residual tumor on postoperative MRI scans. Up to 3 cycles of paclitaxel were administered as a continuous 96-hour intravenous infusion prior to radiation, provided that the tumor did not enlarge on serial MRIs. The initial 10 patients were treated with the previously recommended phase II dose of 140 mg/m2. Less than anticipated toxicity led to the development of a phase I/II study in 24 patients in which paclitaxel doses were escalated separately in patients receiving (+EIAED) or not receiving (-EIAED), concomitant enzyme-inducing antiepileptic drugs. Paclitaxel plasma steady-state concentrations (Css) were measured during the first cycle of chemotherapy. Response was the primary efficacy endpoint for this study, although survival was also assessed. RESULTS: The MTD was 140 mg/m2 in the -EIAED, and 200 mg/m2 in the +EIAED patient groups. The mean Css for the -EIAED patients treated at 140 mg/m2 was 38 nM, whereas the mean Css for +EIAED patients were 17 nm at 140 mg/m2, 27 nM at 175 mg/m2, 46 nM at 200 mg/m2, and 51 nM at 230 mg/m2. One patient, who had a verified partial response, had his diagnosis changed to an anaplastic oligodendroglioma on subsequent central neuropathologic review. None of the 15 assessable glioblastoma patients treated at or above the MTD doses showed a radiographic response to paclitaxel. The median survival of eligible patients on this protocol was 355 days (95% CI, 255 to 485 days), which is similar to the survival of comparable patients treated with conventional therapy. CONCLUSIONS: These results suggest that (1) paclitaxel given as a 96-hour infusion at the MTD has minimal activity in patients with untreated glioblastoma, (2) the concomitant administration of EIAEDs alters the pharmacology of paclitaxel, resulting in a lower Css, reduced systemic toxicity, and higher dose requirements, (3) this study design, in which a new agent is given prior to radiation therapy (with serial monitoring of MRI), did not adversely affect survival in this patient population.

Aged↗

PubMed1997

Prospective detection of preclinical lung cancer: results from two studies of heterogeneous nuclear ribonucleoprotein A2/B1 overexpression.

The United States lung cancer epidemic has not yet been controlled by present prevention and treatment strategies. Overexpression of a Mr 31,000 protein, heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1, had shown promise as a marker of lung cancer. In a pilot study of archived preneoplastic sputum specimens, hnRNP A2/B1 overexpression more accurately detected preclinical lung cancer than standard cytomorphology. In separate, ongoing prospective studies, sputum is collected annually from stage I resected non-small cell lung cancer patients at high risk of developing a second primary lung cancer and Yunnan tin miners at high risk of primary lung cancer. After the first year of follow-up, preclinical detection of lung cancer by routine cytology was compared with hnRNP A2/B1 overexpression as measured by quantitative densitometry of immunostained slides. Up-regulation of hnRNP A2/B1 in sputum specimens accurately predicted the outcome in 32 of 40 primary lung cancer and control patients within 12 months, whereas cytological change suggestive of lung cancer was found in only 1 patient. In the primary lung cancer study, overexpressed hnRNP A2/B1 accurately predicted the outcome in 69 of 94 primary lung cancer and control miners, whereas only 10 with primary lung cancer were diagnosed cytologically. These two prospective studies accurately predicted that 67 and 69% of those with hnRNP A2/B1 up-regulation in their sputum would develop lung cancer in the first year of follow-up, compared with background lung cancer risks of 2.2 and 0.9% (35- and 76-fold increase, respectively). Using sputum cells to monitor hnRNP A2/B1 expression may greatly improve the accuracy of preclinical lung cancer detection.

Aged↗

PubMed1997

Androgen receptor variants with short glutamine or glycine repeats may identify unique subpopulations of men with prostate cancer.

The androgen receptor (AR) contains glutamine (CAG) and glycine (GGC) repeats that are each polymorphic in length. We screened clinically localized prostate cancers for somatic mutations in the length of the CAG and GGC repeats in the AR gene and characterized the length of these repeats in the germ-line AR gene. Somatic mutations were rare, and the range of germ-line repeat lengths in men with prostate cancer was within the range of normal in the general population. Most allele frequencies in Caucasian men with clinical prostate cancer were remarkably comparable to those in the general Caucasian population. However, a subpopulation of the men with clinical prostate cancer had a substantially higher frequency of AR alleles with 16 or 17 CAGs (6 of 59 men, 10%) than did the general population (6 of 370 alleles, 1.6%), and a different subpopulation of the men with prostate cancer had a higher frequency of AR alleles with 12 or 13 GGCs (7 of 54 men, 13%) than did the general population (1 of 110 alleles, 0.9%). Of the men with prostate cancer who had an AR gene with 16 or 17 CAGs, 83% had lymph node-positive disease, despite the lack of clinical evidence of metastatic spread. This suggests that a short AR CAG allele may be a risk factor for the development of clinically unsuspected lymph node-positive prostate cancer among men undergoing radical prostatectomy and raises the question of whether this short repeat length played an active role in the development of aggressive prostate cancer. The odds of having a germ-line AR gene with a short CAG repeat (</=17 CAGs) were substantially higher in Caucasian men with lymph node-positive prostate cancer than in Caucasian men with lymph node-negative disease or in the general Caucasian population. The odds of having a short germ-line AR CAG were the same for men with lymph node-negative prostate cancer as for the general Caucasian population. The odds of having a germ-line AR gene with a short glycine repeat (</=14 GGCs) were substantially higher in men with prostate cancer than in the general population, but the frequency of alleles with a short GGC repeat was the same in men with lymph node-positive versus lymph node-negative disease. This suggests that a short GGC repeat may be a risk factor for the development of clinical prostate cancer, a hypothesis that needs to be tested in cohort and case-control studies.

Adenocarcinoma↗

PubMed1996

Improved designs for dose escalation studies using pharmacokinetic measurements.

We describe a method for incorporating pharmacokinetic (PK) data into dose escalation clinical trial designs. Doing so can improve the efficiency and accuracy of these studies. The method proposed uses a parametric dose response function that models the probability of response in each person with two effects: the dose of drug administered and an ancillary pharmacokinetic measurements. After treatment and observation of each subject (or group of subjects) for response, one calculates the dose to be administered to the next individual (or group) to yield the target probability of response from the current best estimate of the dose-response curve. This procedure is a variant of the continual reassessment method (CRM). Statistical simulations employing a logistic dose-response model (that is, we model the logit of the response probability as a linear combination of predictors), dose of drug, and the area under the time-concentration curve (AUC) demonstrate that the addition of pharmacokinetic information to the CRM is a practical and useful way to improve both dose-response modelling and the design of dose escalation studies.

Area Under Curve↗