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Biomedical subjects

P Bonomi

Publications and source records attributed to P Bonomi.

At least 37 records · Page 2Linked to original sources
PubMed1998

Eastern Cooperative Oncology Group experience with chemotherapy in advanced non-small cell lung cancer.

Eastern Cooperative Oncology Group (ECOG) investigators have tested a variety of single-agent and combination regimens in patients with non-small cell lung cancer (NSCLC) during the last 2 decades. The following observations have been made. (1) The mitomycin/vinblastine/cisplatin regimen produced a trend for higher response rates in two studies and a significantly higher response rate in a third study. Survival, however, tended to be shorter in patients receiving this regimen. (2) Carboplatin produced a 9% overall response rate and a median survival of 31.7 weeks, which was slightly but significantly longer than the median survivals obtained with three combination chemotherapy regimens. (3) Paclitaxel produced an overall response rate of 21% and a 1-year survival rate of 40% in previously untreated NSCLC patients. This observation led to a phase III trial in which paclitaxel (135 mg/m2 and 250 mg/m2) was combined with cisplatin and compared with etoposide/cisplatin. Response rates for each of the paclitaxel/cisplatin regimens (26% for 135 mg/m2 paclitaxel and 31% for 250 mg/m2) were significantly higher than the response rate for etoposide/cisplatin (12%), but response between the two paclitaxel/cisplatin arms was not significantly different. At this point, there is a trend toward longer survival in each of the paclitaxel/cisplatin arms, but the final survival analyses have not been completed. In the next phase III trial, ECOG will evaluate paclitaxel (135 mg/m2) plus cisplatin in comparison to three other regimens--docetaxel/cisplatin, gemcitabine/cisplatin, and carboplatin/paclitaxel.

Antineoplastic Agents↗
PubMed1998

Recent advances with chemotherapy for NSCLC: the ECOG experience. Eastern Cooperative Oncology Group.

Management of disseminated non-small-cell lung cancer has changed over the past 10 years. Newer agents, such as vinorelbine (Navelbine) and paclitaxel (Taxol), have been shown to modestly improve survival in patients with advanced disease when administered in conjunction with cisplatin (Platinol). Compared with older regimens consisting of cisplatin and a Vinca alkaloid or a podophyllotoxin, the newer regimens yield a 10- to 15-week improvement in median survival and an additional 10% to 15% in 1-year survival. Based on these results derived from randomized trials, it appears that metastatic non-small-cell lung cancer patients with good performance status should be treated with regimens containing either vinorelbine or paclitaxel in conjunction with cisplatin.

Antineoplastic Agents, Phytogenic↗
PubMed1998

Review of selected randomized trials in small cell lung cancer.

Approximately 25 years ago, investigators realized that small cell lung cancer was relatively sensitive to chemotherapy. The results of the initial trials showed that median survival duration in extensive-disease patients treated with combination chemotherapy was 8 to 10 months compared with 6 to 8 weeks for untreated patients. Similarly, in limited-disease patients, treatment with combination chemotherapy was associated with a median survival duration of approximately 12 months, while the median survival was approximately 3 to 4 months in patients treated with surgery or radiation therapy alone. Encouraged by the relatively high response rates and improved survival, investigators have conducted a large number of randomized trials that have tested concepts such as the Goldie-Coldman hypothesis and practical issues including chemotherapy dose and schedule, duration of treatment, and combined modality treatment. Selected randomized trials that have addressed important issues will be discussed in this brief review.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

A 5-lipoxygenase inhibitor at micromolar concentration raises intracellular calcium in U937 cells prior to their physiologic cell death.

Micromolar MK886, a selective inhibitor of 5-lipoxygenase at nanomolar concentration, induces physiologic cell death in U937 and chronic myelogenous leukemia blast cells. When U937 cells were challenged with 10 microM MK886, an acute, biphasic and sustained rise in intracellular Ca2+ occurred, as determined with Fura-2. The initial increase was followed by a transient decline and a larger rise due to an influx of external Ca2+. The first increase and part of the subsequent rise also developed in Ca(2+)-free medium, identifying their origin from intracellular stores. The intracellular Ca2+ concentration of U937 cells that remained after culture for 24 or 48 h with 5 or 10 microM MK886 was not reliably altered from the control values of 130 +/- 8.3 nM. Under similar conditions MK886 did not increase cytosol Ca2+ of a human prostate (PC3) cell line examined in suspension. The increase in intracellular Ca2+ in response to MK886 in calcium-containing medium was confirmed with an ACAS laser spectrometer. U937 cytosol pH was measured with the fluorescent probe BCECF, but not persistent acute or chronic change was induced by MK886. The rapid and sustained rise in Ca2+ induced by MK886 is an early event in U937 cells which subsequently undergo physiologic cell death characterized in many by apoptosis.

Amiloride↗
PubMed1997

Postoperative and Preoperative Chemotherapy for Non-Small Cell Lung Cancer.

BACKGROUND: Few randomized trials of preoperative and postoperative adjuvant systemic therapy have been performed in patients with non-small-cell lung cancer (NSCLC). METHODS: The authors reviewed the recent literature on comparative trials and meta-analyses to determine the current status of adjuvant therapy for patients with NSCLC. RESULTS: Postoperative adjuvant therapy with cisplatin-containing regimens reduces the risk of death by 3% at two years and by 5% at five years. Preoperative therapy can clear tumor in the resected specimen in approximately 15% of cases, and two small trials report substantial survival benefit. CONCLUSIONS: The development of new and more active regimens for NSCLC may provide the biologic basis for clinical trials to demonstrate more pronounced benefit for adjuvant systemic therapy.

Journal Article↗
PubMed1997

Regrowth resistance as a likely significant contributor to treatment failure in drug-sensitive neoplastic diseases.

Attempts to improve the effectiveness of therapy for neoplastic diseases have largely focused on increasing the cytotoxic efficacy of therapy. While this approach is logical, there is another approach, based on the concept of regrowth resistance, which offers an alternate means of improving treatment outcome. The term "regrowth resistance" refers to the reduction in treatment efficacy resulting from the regrowth of neoplastic cells between courses of therapy or even between doses of radiation therapy. Regrowth resistance is likely to play a significant role in determining the outcome of treatment in rapidly proliferating neoplasms. A reduction in the rate of tumor regrowth would increase the net effectiveness of cytotoxic therapy and would also inhibit the development of resistance to cytotoxic therapies.

Cell Division↗
PubMed1997

Cisplatin/etoposide vs paclitaxel/cisplatin/G-CSF vs paclitaxel/cisplatin in non-small-cell lung cancer.

A phase III trial conducted by Eastern Cooperative Oncology Group (ECOG) investigators assessed the possible impact of paclitaxel on survival, response, and toxicity in patients with advanced non-small-cell lung cancer. Three regimens were compared: cisplatin/etoposide, paclitaxel/ cisplatin/granulocyte colony-stimulating factor (G-CSF), and paclitaxel/ cisplatin. Patients were randomly assigned to the regimens, each of which was repeated every 21 days over a 17-month period. Response rates were 12% in the cisplatin/etoposide group, 31% in the paclitaxel/cisplatin/G-CSF group, and 26% in the paclitaxel/cisplatin group. Significant differences in response were observed between the cisplatin/etoposide and paclitaxel/cisplatin/G-CSF groups and the cisplatin/etoposide and paclitaxel/cisplatin groups; there was no significant difference between patients treated with paclitaxel/cisplatin vs paclitaxel/cisplatin/G-CSF. Both paclitaxel regimens were associated with significantly higher response rates compared with etoposide/cisplatin. Based on preliminary survival analyses, the investigators concluded that the paclitaxel regimens may be associated with superior survival.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1997

Postoperative bronchopulmonary complications in stage III lung cancer patients treated with preoperative paclitaxel-containing chemotherapy and concurrent radiation.

We previously observed encouraging results and acceptable toxicity in phase II trials testing preoperative split-course thoracic radiation and simultaneous cisplatin, etoposide, and 5-fluorouracil in stage III non-small cell lung cancer patients. We decided to delete 5-fluorouracil and to incorporate paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) into our combined-modality treatment. The first group of patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 2, etoposide 50 mg orally days 1 to 5 and 8 to 12, cisplatin 50 mg/m2 on day 21, and paclitaxel 35 mg/m2 escalated to 45 mg/m2 on days 1 and 8. Group 2 patients received carboplatin dosed at an area under the concentration-time curve of 4 on day 1, etoposide 45 mg/m2 intravenously daily on days 2 to 5, and paclitaxel 80 mg/m2 (escalating to 120 mg/m2) on day 1. Patients in group 3 received carboplatin dosed at an area under the concentration-time curve of 4 on day 1 and paclitaxel 120 mg/m2 (escalating to 140 mg/m2) on day 1. Each patient received radiation 2 Gy daily on days 1 to 5 and 8 to 12, and a total of two cycles was given at 28-day intervals. Twenty-one patients received preoperative chemoradiotherapy: group 1, five patients; group 2, 11 patients; and group 3, five patients. Thoracotomy was not done in five patients due to cerebrovascular accident in one and progressive tumor in four. The remaining 16 patients had the following procedures: pneumonectomy, eight; lobectomy, six; chest wall resection, one; and no resection, one. Postoperative complications included bronchopleural fistula in one patient each in groups 1 and 3, hypoxia in one patient in group 1, pulmonary hypertension in one patient in group 2, pneumonia in one patient in group 2, and adult respiratory distress syndrome in one patient in group 3, which proved lethal. Thus, six of 16 patients had serious postoperative complications. The relatively high incidence of postoperative bronchopulmonary complications suggests that the use of preoperative paclitaxel-containing chemotherapy and simultaneous thoracic radiation may not be feasible.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1996

Fadrozole HCL (CGS-16949A) versus megestrol acetate treatment of postmenopausal patients with metastatic breast carcinoma: results of two randomized double blind controlled multiinstitutional trials.

BACKGROUND: Breast cancer patients with prior response to endocrine therapy achieve subsequent benefit from additional endocrine therapies. The efficacy and safety of an aromatase inhibitor, fadrozole HCL, were compared with megestrol acetate in post menopausal patients who had disease progression after receiving antiestrogen therapy either for metastatic disease or as adjuvant therapy. METHODS: In 2 multiinstitutional prospective trials, 683 postmenopausal patients were randomized to receive either fadrozole HCL, 1 mg twice daily, or megestrol acetate, 40 mg 4 times daily, in a double blind fashion after progression on first-line hormonal therapy. Objective response rates, time to progression, survival and safety of the two regimens were compared. RESULTS: Results of intent-to-treat analyses are presented in this study. No significant differences were detected between the two treatment groups in time to progression, objective response rates, duration of response, and survival in either trial. There were no clinically meaningful differences between the treatment groups in the incidence and severity of adverse experiences, except that weight gain, fluid retention, and dyspnea were observed in more patients in the megestrol acetate group compared with those receiving fadrozole HCL, whereas nausea and vomiting were observed in more patients in the fadrozole HCL group compared with those receiving megestrol acetate. CONCLUSIONS: Fadrozole HCL was as efficacious as megestrol acetate in postmenopausal patients with metastatic breast carcinoma after one hormonal therapy. Adverse experiences were mild with both therapies, but megestrol acetate was associated wiht a higher frequency of weight gain, fluid retention and dyspnea, whereas fadrozole HCL was associated with a higher frequency of nausea and vomiting.

Adult↗
PubMed1996

Does an inability to eradicate normal stem cells preclude the cure of some cancers?

Presently, identified signal transduction pathways do not alter normal stem-cell survival. With prostate cancer as a model, the argument is advanced that an inability to eradicate normal androgen-dependent prostate stem-cells precludes successful treatment of transformed, androgen-independent and metastatic progeny. While applying this idea to cancers of non-essential organs or to endocrine cancers seems feasible, the inutility of this approach for most other malignancies appears likely, although not certain.

Animals↗
PubMed1996

Chemotherapy for Stage IV Non-Small Cell Lung Cancer: Protocol Versus Nonprotocol? Is Noninvestigational Treatment Worthwhile? Patient Selection? Which Regimen? What's Next?

The results of selected chemotherapy trials and philosophical considerations regarding the role of chemotherapy in Non-Small Cell Lung Cancer are discussed in this review. The issue of treating patients within a clinical or with a "standard regimen" is addressed. In addition, the survival results of randomized trials in which chemotherapy was compared with supportive care and the related quality of life and economic concerns are reviewed. Physicians' attitudes regarding treating advanced non-small cell lung cancer patients as well as the questions of patient selection and the choice of regimen including the consideration of single versus combination regimens are discussed. The results of single agent phase II trials that identified new agents with response rates >/=15%-paclitaxel, docetaxel, vinorelbine, gemcitabine, CPT11-are described, and their implications for the design of new clinical trials are discussed.

Journal Article↗
PubMed1996

Escalating paclitaxel doses combined with carboplatin/etoposide and thoracic radiotherapy as preoperative or definitive treatment for stage III non-small cell lung cancer.

We have evaluated escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) in combination with carboplatin, cisplatin, etoposide, and concurrent thoracic radiotherapy in patients with stage III non-small cell lung cancer. Dose-limiting toxicity was observed at paclitaxel 90 mg/m2. Subsequent modifications resulted in a new regimen, which consists of a 3-hour paclitaxel infusion on day 1 (three dose levels: 80, 100, and 120 mg/m2), etoposide 40 mg/m2 intravenously over 1 hour daily on days 2 to 5, and carboplatin given at an area under the concentration-time curve of 4 mg/mL x min on day 1 after paclitaxel. Treatment courses were repeated every 28 days. Eleven patients considered eligible for surgery received two courses. Nonsurgical patients (five) received three courses. No episodes of grade > or = 3 nausea and vomiting, dermatitis, anorexia, esophagitis, or thrombocytopenia were observed. The dose-limiting toxicity (grade 4 granulocytopenia) occurred in three of five patients at 120 mg/m2 paclitaxel (level 3). Grade 3 radiation pneumonitis was observed in three patients. Nine patients have undergone pulmonary resection: four pneumonectomies, four lobectomies, and one segmental resection. No operative deaths, respiratory insufficiency, or cardiovascular complications were observed. Clinical partial remissions have been observed in 11 of 16 patients overall, and two histologic complete remissions were achieved in nine surgical patients. Our preliminary results show that pulmonary resection is feasible following treatment with radiation and concurrent paclitaxel-containing chemotherapy. Although the maximum tolerated paclitaxel dose in the present study was relatively low, favorable initial responses warrant further study of paclitaxel-containing combination chemotherapy and concurrent radiation. We next plan to delete etoposide from our chemoradiotherapy regimen and escalate the paclitaxel dose.

Agranulocytosis↗
PubMed1995

Phase II trial of gallium nitrate, amonafide and teniposide in metastatic non-small cell lung cancer. An Eastern Cooperative Oncology Group study (E2588).

Fifty-five patients with metastatic non-small cell lung cancer (NSCLC) were entered into this phase II randomized study for evaluating three new agents: gallium nitrate, amonafide and teniposide. The patients had to have ECOG performance status 0 or 1, no prior chemotherapy, and adequate hematological, hepatic and renal functions. Forty-seven patients were eligible and evaluable. Fourteen were randomized to receive gallium nitrate, 18 to amonafide and 15 to teniposide. Seventy-four percent of eligible patients were male. The majority of patients (89%) had an ECOG performance status 1. ECOG grade 4 toxicity occurred twice in patients on gallium nitrate, seven times on amonafide and 18 times on teniposide. The cause of death was attributed to amonafide in one patients (from sepsis) and to teniposide in two patients (due to infection and leukopenia). There was no objective response in all the patients entered. The overall survival times ranged from 2 weeks to 156 weeks with a medium of 23 weeks. There were no survival differences among the three treatment arms. We conclude that gallium nitrate, amonafide and teniposide are inactive in metastatic NSCLC and do not warrant any further testing in this disease.

Adenine↗
PubMed1995

Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument.

The FACT-L (version 3) is a 44-item self-report instrument which measures multidimensional quality of life. Available in eight languages, it is currently being used in several Phase II and III lung cancer clinical trials. Reliability and validity of the 33-item version 2 of the FACT-General (FACT-G) have previously been published. This paper reports further validation data on the FACT-G with a subsample of lung cancer patients from the original publication and, more importantly, presents data on the Lung Cancer Subscale (LCS). The nine LCS questions were administered along with the FACT-G to 116 patients with lung cancer. Internal consistency (coefficient alpha) was improved from 0.53 to 0.68 by dropping two questions which were uncorrelated with the others. A subset of 41 patients was tested again at 2 months to evaluate sensitivity to change in performance status rating (PSR) and to obtain estimates of a clinically meaningful change score for the FACT-G and the 7-item LCS. Using a linear test for trend, sensitivity to change in performance status rating (PSR) was obtained with the Total score (P = 0.03), the Physical Well Being (PWB) subscale (P = 0.02), the Functional Well Being (FWB) subscale (P = 0.05), and the LCS (P = 0.03). A 21-item Trial Outcome Index (TOI), combining scores on PWB, FWB and LCS, was highly reliable (coefficient a = 0.89) and sensitive to change in PSR F(1,38) = 4.84 (P = 0.01). This TOI is probably the most relevant and precise indicator of patient-reported quality of life available for lung cancer patients who complete the FACT-L while participating in an oncology clinical trial. The FACT-L may also be of benefit in evaluating quality of life in patients with lung diseases other than cancer.

Adult↗
PubMed1995

Combined modality treatment for stage III non-small cell lung cancer.

There are increasing reports of studies in which combined modality treatment is being tested in stage III non-small cell lung cancer. Randomized trials in which sequential chemoradiotherapy has been compared to radiation alone and in which single agent cisplatin and simultaneous thoracic radiation were compared to radiation are reviewed and discussed. The largest and the most mature phase II trials of preoperative chemotherapy are also included in this review. Similarly the results from recently reported small randomized trials evaluating preoperative treatment are described. Potential future directions for clinical trials are suggested, including the incorporation of new agents in combined modality regimens.

Antineoplastic Agents↗
PubMed1995

Carboplatin/etoposide/radiation plus escalating doses of paclitaxel in stage III non-small cell lung cancer: a preliminary report.

Large randomized studies have shown superior survival results for sequential chemoradiotherapy compared with radiation alone in stage III non-small cell lung cancer. Similarly, chemotherapy followed by surgery was associated with longer survival than surgery alone in small randomized trials. Despite these results, disease recurs in most stage III patients. To improve these results, we are studying escalating doses of paclitaxel (Taxol; Bristol-Myers Squibb Company, Princeton, NJ) combined with platinum/etoposide and simultaneous thoracic irradiation as preoperative and curative therapy. Initially, paclitaxel was given at a starting dose of 35 mg/m2 intravenously (i.v.) over 24 hours on days 1 and 8; carboplatin (area under the concentration time curve) 4 mg/mL.min) i.v. was given on day 2 and etoposide 5 mg/d orally on days 1 to 5 and 8 to 12; cisplatin 50 mg/m2 i.v. was given on day 23, and radiation 2 Gy was given on days 1 to 5 and 8 to 12. Courses were repeated every 28 days. Four of five patients treated at the second paclitaxel dose level (90 mg/m2) experienced grade 4 toxicity. The treatment regimen was changed to paclitaxel given at a starting dose of 80 mg/m2 i.v. over 3 hours on day 1, carboplatin (area under the concentration time curve 4 mg/mL.min) i.v. given immediately after paclitaxel, etoposide 40 mg/m2 i.v. given over 1 hour on days 2 to 5, and radiation 2 Gy given on days 1 to 5 and 8 to 12. No grade 4 toxicity was observed in five patients treated at the first paclitaxel dose level (80 mg/m2). After two courses, pulmonary resection (lobectomy and pneumonectomy) was performed without fatalities in five patients. Although more data are needed, pulmonary resection appears feasible following treatment with this paclitaxel-containing regimen. Patient accrual is continuing to determine the maximum tolerated dose of paclitaxel.

Administration, Oral↗
PubMed1994

Combined modality treatment using BID radiation for locally advanced non-small cell lung carcinoma.

BACKGROUND: From February 1988 to August 1991, 82 patients were treated on Phase II trial of split-course multimodality treatment for locally advanced, non-small cell lung cancer (NSCLC). METHODS: Treatment consisted of twice-daily radiation (150 cGy/fraction) delivered with concomitant infusional cisplatin, etoposide, and fluorouracil for 1 week every third week. Patients were classified before initial treatment as either potentially resectable (eligible for surgery [ES]) or ineligible for surgery (IES). The ES group consisted of 38 Stage IIIA and 7 Stage IIIB patients. The IES group had 5 patients staged as IIIA and 32 staged as IIIB. Most patients were staged clinically. ES patients received three cycles of treatment (39 Gy) before resection. IES patients received four cycles (60 Gy) delivered with curative intent. RESULTS: Thirty-nine of 45 ES patients underwent resection. The pathologic response rate was 27%. Three-year actuarial local control was 86% for 41 evaluable ES patients. Three-year actuarial survival for the whole ES group was 39%, with a median follow-up for living patients of 32 months. The IES group faired less well, with an 18% 3-year actuarial survival. Treatment was well tolerated with a median weight loss of one-half pound, mild or moderate pneumonitis in 5%, mild esophagitis in 15%, and severe nausea and/or vomiting in 10% of patients. Treatment-related mortality was 5%. CONCLUSIONS: Patients treated with conventional radiation alone for Stage III NSCLC are rarely cured. This well tolerated Phase II study demonstrated encouraging results for such patients. Both local control and survival appeared promising, especially in patients rendered resectable after combined-modality treatment.

Adult↗