Biomedical subjects

G T Budd

Publications and source records attributed to G T Budd.

At least 55 records · Page 3Linked to original sources

PubMed1995

Accelerated induction therapy and resection for poor prognosis stage III non-small cell lung cancer.

BACKGROUND: Induction therapy and resection may improve the survival of patients with poor prognosis stage III non-small cell lung cancer, at the cost of significant treatment prolongation. The purpose of this study was to assess toxicity, response, and survival of an accelerated induction regimen and resection in poor prognosis stage III non-small cell lung cancer. METHODS: Forty-two surgically staged patients with poor prognosis stage III non-small cell lung cancer received 11 days of induction treatment consisting of 96 hours of continuous chemotherapy infusions of cisplatin (20 mg.m-2.day-2), 5 fluorouracil (1,000 mg.m-2.day-2), and etoposide (75 mg.m-2.day-2) concurrent with accelerated fractionation radiation therapy (1.5 Gy twice a day, to a dose of 27 Gy). Induction was followed in 4 weeks by resection. Postoperatively, a second course of continuous chemotherapy and concurrent accelerated fractionation radiation therapy (postoperative dose 13 to 36 Gy) was given. RESULTS: Despite some degree of induction toxicity in all patients there was only one induction death (2.4%). A clinical partial response was seen in 24 patients (57%). Thirty-six patients (86%) underwent thoracotomy, and resection was possible in 33 (79%). Pathologic downstaging was seen in 17 patients (40%), and 2 patients (5%) had no residual carcinoma at operation. There were 11 postoperative complications (31%) and 4 postoperative deaths (11%). Thirteen patients (31%) are alive and disease-free, 24 (57%) have persistent disease or have recurred (15 distant, 5 locoregional, 4 both), and 9 patients are alive with disease. The median survival is 21 months and the 2-year Kaplan-Meier survival is 43%, with no differences identified between stages IIIA and IIIB patients (p = 0.63). CONCLUSIONS: We conclude that accelerated induction therapy and resection in poor prognosis stage III non-small cell lung cancer (1) is toxic, with a 12% treatment mortality; (2) is effective with a 79% resection rate and 40% pathologic downstaging rate; (3) provides excellent local control; (4) may prolong survival; and (5) is of value in stage IIIB as well as stage IIIA patients.

Adult↗

PubMed1995

Short-course FAC-M versus 1 year of CMFVP in node-positive, hormone receptor-negative breast cancer: an intergroup study.

PURPOSE: To compare 1 year of therapy with continuous cyclophosphamide, methotrexate, fluorouracil (5-FU), vincristine, and prednisone (CMFVP) with a short course of treatment with a doxorubicin-based regimen in the postsurgical adjuvant treatment of patients with hormone receptor-negative, node-positive breast cancer. PATIENTS AND METHODS: Five-hundred thirty-one eligible women with hormone receptor-negative, node-positive breast cancer were randomized to receive either 1 year of therapy with CMFVP or 20 weeks of therapy with four 5-week courses of treatment with 5-FU, doxorubicin, cyclophosphamide, and methotrexate (FAC-M). RESULTS: At a median follow-up time of 4.9 years, the two treatment arms cannot be demonstrated to be different with respect to overall survival (stratified log-rank, P = .27). The 5-year survival rate is 64% on the CMFVP arm and 61% on the FAC-M arm. CMFVP produces marginally superior disease-free survival (P = .06). The estimated 5-year disease-free survival rate is 55% for patients treated with CMFVP as opposed to 50% for patients treated with FAC-M. CONCLUSION: Neither regimen was shown to be superior in terms of overall survival. Because the disease-free survival produced by CMFVP is marginally superior to that produced by FAC-M, we do not recommend FAC-M for further investigation or for routine use. Possible implications of this study are discussed in the context of other adjuvant chemotherapy trials.

Adult↗

PubMed1995

Palliative chemotherapy of adult soft tissue sarcomas.

Sarcomas represent approximately 1% of adult malignancies. Surgery and local radiotherapy are the mainstays of therapy, as treatment of metastatic disease is palliative in intent in most cases. The value of adjuvant chemotherapy is controversial. Most adjuvant trials using single-agent doxorubicin have failed to show improved relapse-free and overall survival. Minor advantages in relapse-free survival have been reported in some adjuvant chemotherapy trials using combination chemotherapy. Further research is needed to develop effective adjuvant regimens. Surgery also may be important in the treatment of metastatic disease, as approximately 20% of patients with pulmonary metastases amenable to resection may be rendered disease free for prolonged periods. Chemotherapy is of modest value. Only three drugs (doxorubicin, dacarbazine, and ifosfamide) have clear activity in the treatment of adult soft tissue sarcomas. Combination chemotherapy may be associated with higher objective response rates than single-agent chemotherapy, but toxicity also is greater with combination regimens and no survival advantage for the more aggressive alternatives has been reproducibly reported. In patients over the age of 50 years, single-agent chemotherapy may be preferable to combination chemotherapy. Combination chemotherapy, often with aggressive supportive measures, may be considered in younger patients with a good performance status. New active agents need to be identified if therapy of this group of diseases is to be improved.

Adult↗

PubMed1994

Estrogen receptor mutations in tamoxifen-resistant breast cancer.

Clinical resistance to antiestrogens like tamoxifen is a major problem in the treatment of hormone-dependent breast cancers. Since the estrogen receptor plays a central role in mediating the effects of estrogens and antiestrogens, we hypothesized that mutations in the estrogen receptor could be one mechanism by which breast tumors evolve from a hormone-dependent to a hormone-independent phenotype. The eight exons of the estrogen receptor complementary DNA from 20 tamoxifen-resistant and 20 tamoxifen-sensitive tumors were screened by Single Strand Conformation Polymorphism (SSCP), and the variant conformers were sequenced to identify the nucleotide changes. A 42-base pair replacement was found in exon 6 of a tamoxifen-resistant tumor. A single base pair deletion in exon 6 of a tamoxifen-resistant metastatic tumor but not in the primary tumor was detected in another case. If translated, both these mutations could generate truncated receptors with an intact DNA-binding domain and a defective hormone-binding domain that could constitutively activate transcription of previously estrogen-responsive genes. The remaining 18 of 20 tamoxifen-resistant tumors did not contain mutations in any of the 8 exons of the estrogen receptor complementary DNA. These results suggest that mutations in the estrogen receptor occur at a low frequency and do not account for most estrogen-independent, tamoxifen-resistant breast tumors.

Amino Acid Sequence↗

PubMed1994

Amifostine: potential for clinically useful cytoprotection.

The ability to target malignant cells for cytotoxicity while sparing normal host tissues has proven to be limited. These limitations have resulted in unacceptable toxicity or insufficiently effective therapy. Continuing investigation of new, potentially useful cytotoxic agents must continue. An alternative approach, also worthy of study, is the selective protection of normal tissues. This approach, used in conjunction with available therapeutic agents, may open the therapeutic window and incrementally enhance the effectiveness of cytotoxic therapy. A variety of methods have been used to protect normal tissues selectively. Regional protection can be used for certain organ systems, such as the oral mucosa. Selective protection on a systemic level is more difficult but agents that seem to protect normal but not malignant tissues selectively are being developed. Among these is amifostine, which was originally selected by the U.S. defense department for study as a radioprotectant. Pre-clinical studies have suggested that amifostine is differentially concentrated in normal tissues but not in malignant tissues. Tissue-specific differences in the activity of alkaline phosphatase, which dephosphorylates amifostine to its active metabolite WR-1065, and in pH are thought to be involved in this relative specificity. Clinical studies indicate that amifostine can reduce the myelosuppression produced by cyclosphosphamide, the combination of cyclophosphamide and cisplatin, and, perhaps, carboplatin. The protective effects of amifostine on nonhematopoietic toxicities are being investigated. Future trials will investigate the integration of amifostine with cytokine-based supportive care in order to define the role of this potentially clinically useful cytoprotectant agent.

Amifostine↗

PubMed1994

Phase I/II trial of dipyridamole, 5-fluorouracil, leukovorin, and mitoxantrone in metastatic breast cancer.

Based upon the hypothesis that dipyridamole would potentiate the cytotoxicity of mitoxantrone and the combination of 5-fluorouracil (5-FU) and leukovorin, we performed a phase I/II trial of the combination of dipyridamole, 5-FU, leukovorin, and mitoxantrone in patients with metastatic breast cancer. The dose of dipyridamole was fixed at 175 mg/m2 by mouth every 6 h (700 mg/m2/day), based upon a previous phase I trial of oral dipyridamole with 5-FU and leukovorin. Dipyridamole therapy began 24 h prior to the first dose of chemotherapy and continued until 24 h after the last dose of chemotherapy for each course of treatment. At the initial dose level, leukovorin 200 mg/m2 was given intravenously immediately prior to 5-FU 375 mg/m2 intravenously on days 1-5. Mitoxantrone 6 mg/m2 was given as a single dose on day 3. Unacceptable toxicity was observed at this dose level, leading to successive dose decrements rather than dose increments. The maximum tolerated dose was leukovorin 200 mg/m2 days 1-2, 5-FU 375 mg/m2 days 1-2, mitoxantrone 6 mg/m2 on day 2, and dipyridamole 175 mg/m2 every 6 h on days 0-3. Two responses were produced in 15 patients. This regimen is not recommended for further investigation in the treatment of breast cancer.

Adult↗

PubMed1994

A phase I trial of intrapleural recombinant human interferon alpha (rHuIFN alpha 2b) in patients with malignant pleural effusions.

The use of intrapleural sclerosing agents to control reaccumulation of pleural fluid in patients with malignant effusions has been widely investigated. A phase I trial of intrapleural recombinant human interferon alpha (rHuIFN alpha 2b) was initiated to determine the toxicity and maximal tolerated dose in this group of patients. rHuIFN alpha 2b was instilled as a single dose following chest tube (15/16) or percutaneous (1/16) drainage of cytologically proven malignant effusions. Doses of rHuIFN alpha 2b were escalated from 25 x 10(6) to 200 x 10(6) U/m2 in cohorts of three to four patients. Toxicity was mild to moderate, and included chills, fever and chest pain, and resembled that produced by systemic administration of rHuIFN alpha 2b. Dose-limiting toxicity occurred at 200 x 10(6) U/m2 and consisted of hepatic enzyme elevations and renal failure. Partial control of the effusions was noted in two patients, with two additional patients having stable disease. Phase II trials of rHuIFN alpha 2b should utilize up to 150 x 10(6) U/m2 for intrapleural instillation.

Adult↗

PubMed1994

Phase I trial of subcutaneous recombinant macrophage colony-stimulating factor: clinical and immunomodulatory effects.

PURPOSE: Recombinant human macrophage colony-stimulating factor (rM-CSF) has been demonstrated to control the growth, differentiation, and function of mononuclear phagocytes. Preclinical studies have indicated antitumor effects, and therefore a phase I trial of rM-CSF in patients with malignancy was initiated. The toxicity and hematologic and immunologic effects were investigated. PATIENTS AND METHODS: rM-CSF was administered as a subcutaneous injection on days 1 through 5 and 8 through 12. Cycles were repeated every 28 days. Cohorts of four to seven patients received rM-CSF at dose levels from 0.1 to 25.6 mg/m2/d. Forty-two patients received 88 cycles of rM-CSF. All patients had metastatic solid tumors refractory to standard therapy. RESULTS: The toxicity of rM-CSF was mild. Dose-limiting toxicity included thrombocytopenia (two patients) and iritis (one patient) occurring at a dose of 25.6 mg/m2/d. Hematologic studies demonstrated dose-related monocytosis occurring routinely at doses > or = 3.2 mg/m2/d, and thrombocytopenia. Immunologic studies demonstrated enhanced secretion of tumor necrosis factor-alpha (TNF-alpha) and interleukin-1-beta (IL-1 beta) by monocytes after in vitro stimulation with lipopolysaccharide, and increased expression of TNF-alpha mRNA at higher rM-CSF dose levels. Pharmacokinetic studies demonstrated that the systemic clearance rate of M-CSF increases during week 1 of therapy, resulting in lower blood levels of M-CSF during the second week of therapy. CONCLUSION: rM-CSF can be safely administered to patients, and has biologic activity on peripheral-blood monocytes.

Adult↗

PubMed1993

Phase I trial of recombinant granulocyte-macrophage colony-stimulating factor in patients with lung cancer: clinical and immunologic effects.

Recombinant granulocyte-macrophage colony-stimulating factor (rhuGM-CSF) may enhance the functional activity of monocytes and macrophages in vitro and in vivo and thereby have antitumor activity. A phase I trial using rhuGM-CSF was performed; the trial included 17 patients with unresectable and/or metastatic lung cancer. rhuGM-CSF was administered as a continuous infusion for 14 days at four dose levels: 60 micrograms/m2, 125 micrograms/m2, 250 micrograms/m2, and 500 micrograms/m2. Dose-limiting toxicity was pulmonary and occurred at 500 micrograms/m2, with the maximal tolerated dose (MTD) identified as 250 micrograms/m2. The hematologic effects of rhuGM-CSF included leukocytosis with significant correlations between dose level and the numbers of neutrophils, monocytes, eosinophils, and lymphocytes. Bronchoalveolar lavage was performed for 14 patients, and no effect on alveolar macrophage numbers was detected. Tumor biopsies were obtained in two patients, and no changes in macrophage infiltrates were detected with use of immunohistochemical studies. Serum levels of GM-CSF reached a steady state during week one and decreased or were undetectable during week two. No evidence of tumor regression was seen. rhuGM-CSF when administered as a continuous infusion was well tolerated and appears to modulate monocyte numbers and function in vivo.

Adult↗

PubMed1993

Interleukin-2: use in solid tumors.

Recombinant interleukin-2 (rIL-2) is a cytokine that has a central immunoregulatory role in controlling T cell function and growth. Clinical trials of rIL-2 regimens in various solid tumors have been initiated, and 337 patients at the Cleveland Clinic Foundation have been treated in a sequence of trials. The studies have involved rIL-2 or polyethylene-glycol conjugated rIL-2 (PEG-IL-2) as single agents, combinations of rIL-2 with recombinant interferon alpha, IL-4, or doxorubicin, and trials of rIL-2 with tumor infiltrating lymphocytes (TILs). These studies are summarized and involve Phase I or Phase II investigations in patients with renal cell carcinoma (191 patients), malignant melanoma (49 patients) or miscellaneous solid tumors (97 patients). Response rates in each category, respectively, were 12%, 20% and 2%. Toxicity varied depending on the regimen and generally reflected the dose and schedule of rIL-2 being employed. This series of clinical studies demonstrates the role of rIL-2 in various malignancies and documents the activity in patients with malignant melanoma and renal cell carcinoma. Additional studies to investigate potential mechanisms of antitumor activity and response determinants are underway.

Clinical Protocols↗

PubMed1993

Phase II trial of doxorubicin and trifluoperazine in metastatic breast cancer.

Pre-clinical and clinical studies have shown that trifluoperazine (TFP) can modulate multidrug resistance. We have performed a Phase II trial of TFP and doxorubicin in doxorubicin-naive patients with metastatic breast cancer. We hypothesized that TFP would inhibit the development of doxorubicin resistance, resulting in an increased rate of complete response or a prolongation in response duration. Twenty patients with metastatic breast cancer were treated every 3 weeks with TFP 5 mg by mouth every 6 hours on days 0-5 and doxorubicin 60 mg/m2/96 hr on days 1-4 by continuous intravenous infusion. The first 5 patients were treated with TFP 15 mg by mouth every 6 hours, but the dose was reduced to 5 mg every 6 hours when grade 3-4 extrapyramidal toxicity was noted in 3 of the first 5 patients. Thereafter, neurologic toxicity was grade 0-2. No complete and 9 partial responses were produced in 20 patients (45%). The median response duration was 17 weeks (range 7-112). The combination of trifluoperazine and doxorubicin did not seem to produce a response rate or duration markedly different than that expected for doxorubicin alone in patients with metastatic breast cancer. Alternative trial designs may be necessary in future clinical trials investigating the inhibition of acquisition of drug resistance.

Adult↗

PubMed1993

Phase I study of WR-2721 and carboplatin.

Because WR-2721 reduces the toxicity of cisplatin and carboplatin in preclinical systems, we have treated 35 patients in a phase I study of WR-2721 and carboplatin. As the plasma half-life of WR-2721 is short relative to that of carboplatin, WR-2721 was administered in two divided doses. This schedule produced acceptable toxicity in 24 patients treated with carboplatin 400 mg/m2 and escalating doses of WR-2721. In the subsequent 11 patients, WR-2721 was fixed at 740 mg/m2/dose and the dose of carboplatin was escalated. With WR-2721, grade 3-4 thrombopenia (platelets < 50 x 10(9)/l) was produced in 4/5 patients treated with carboplatin 625 mg/m2 and in 1/6 patients treated with carboplatin 500 mg/m2. Carboplatin pharmacokinetic parameters in 4 patients were similar to those reported for carboplatin alone. These results suggest that WR-2721 might increase the maximum tolerated dose of carboplatin from 400 to 500 mg/m2.

Adult↗

PubMed1993

Immunomodulatory effects of recombinant interleukin-3 treatment on human alveolar macrophages and monocytes.

The purpose of these studies was to examine the effects of in vivo and in vitro recombinant IL-3 treatment on alveolar macrophage and monocyte activities associated with antitumor and antimicrobial properties. Alveolar macrophages and blood monocytes from 6 patients receiving IL-3 (125-500 micrograms/m2/day) subcutaneously were isolated before therapy and at various times during the 15 days of therapy. Results indicated that tumor necrosis factor-alpha (TNF), interleukin-1 beta (IL-1), and interleukin-6 (IL-6) secretion were enhanced from monocytes of all patients and from alveolar macrophages of patients receiving 500 micrograms/m2/day IL-3. Constitutive cytokine gene expression was present before therapy, but further enhancement was not detectable during therapy, suggesting a rapid time course of cytokine gene transcription and translation. Serum neopterin levels were elevated 2-5 fold in all patient compatible with the presence of augmented monocyte/macrophage activity. Peak levels of neopterin did not coincide with peak levels of cytokine secretion. In vitro studies of IL-3-treated normal alveolar macrophage and monocyte population demonstrated that IL-3 significantly augmented TNF and IL-6 secretion in monocytes, but not in alveolar macrophages. These differences in alveolar macrophage cytokine secretion observed after in vivo and in vitro IL-3 treatment may reflect the involvement of other cell populations in IL-3 modulation of alveolar macrophages in vivo. Monocytes, in contrast were comparably activated by IL-3 whether presented in vitro or in vivo.

Biopterins↗

PubMed1993

Phase II trial of ifosfamide and cisplatin in the treatment of metastatic sarcomas: a Southwest Oncology Group study.

The Southwest Oncology Group (SWOG) performed a phase II trial of a combination of ifosfamide/mesna/cisplatin in patients with metastatic soft-tissue sarcoma who had previously received one chemotherapeutic regimen. A total of 39 patients were registered in the study, including 7 treated during a limited-institution pilot phase; 38 patients were fully eligible and evaluable. During the pilot phase, patients were treated with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on days 2 and 9. Due to excessive myelosuppression, the day-9 cisplatin dose was dropped when the study was opened groupwide, and the subsequent 32 patients were treated at 3- to 4-week intervals with 2.5 g/m2 ifosfamide daily on days 1-3, 2.5 g/m2 mesna daily on days 1-4, and 100 mg/m2 cisplatin on day 2. Myelosuppression was severe, with granulocytopenia (< 0.5 x 10(9)/l) being observed in 26 of 38 patients. Three cases of National Cancer Institute grade 3 or 4 nephrotoxicity (serum creatinine, > 3 times the normal value) and three cases of grade 3 or 4 central nervous system toxicity were reported. Overall, three complete and five partial responses were achieved, for a major response rate of 21%. The median survival of all patients was 11 months. We conclude that ifosfamide-based chemotherapy can produce objective responses in previously treated patients with metastatic soft-tissue sarcoma but that cisplatin increases the toxicity of therapy. Phase II trials of new agents are needed to identify drugs with clinical activity in the treatment of soft-tissue sarcomas.

Adolescent↗

PubMed1992

A phase I trial of 5-fluorouracil, folinic acid, and alpha-2a-interferon in patients with metastatic colorectal carcinoma.

The mechanisms of biochemical modulation of 5-fluorouracil (5-FU) cytotoxicity by folinic acid (FA) have been elucidated, and the clinical use of this combination has improved response rates and survival in patients with metastatic colorectal cancer. Recently, Phase II trials also showed potential synergism between alpha-2a-interferon (rHuIFN-alpha 2a) and 5-FU. Therefore, a Phase I trial of these three agents 5-FU, FA, and rHuIFN-alpha 2a was conducted in patients with metastatic colorectal cancer. The drugs were given over 5 days, with dose escalation of either rHuIFN-alpha 2a or 5-FU. Fifty-five eligible patients were treated at eight dosing levels. The maximal tolerated dose (MTD) was as follows: 5-FU 430 mg/m2/d intravenously (IV) on days 1 to 5, FA 200 mg/m2 IV on days 1 to 5, and rHuIFN-alpha 2a 4.0 x 10(6) U/m2/d subcutaneously on days 1 to 5. The dose-limiting toxicities were mucositis and neutropenia. Objective responses were seen at most dosing levels, and overall 15 of 55 patients (27%; 95% confidence interval, 16% to 41%) responded (median duration, 6.5 months). A Phase II trial using the MTD is ongoing.

Adult↗

PubMed1992

Phase I trial of high-dose bolus interleukin-2 and interferon alfa-2a in patients with metastatic malignancy.

PURPOSE: Based on preclinical evidence that the antitumor effects of the combination of interleukin-2 (IL-2) and interferon alfa (IFN alpha) are greater than those of either cytokine alone, we have performed a phase I trial of recombinant IL-2 (rIL-2) and recombinant human IFN alpha 2a (rHuIFN alpha 2a) in patients with refractory malignancies. This study was an extension of an earlier trial that identified reversible myelosuppression as the dose-limiting toxicity of this combination. The present trial used modified definitions of unacceptable toxicity to allow exploration of higher doses of rIL-2. PATIENTS AND METHODS: Both rHuIFN alpha 2a 10.0 x 10(6) U/m2 intramuscularly (IM) and rIL-2 were administered three times weekly for 4 consecutive weeks. IL-2 was given by intravenous (IV) bolus injection at doses that were escalated in successive cohorts of four to six patients, provided that toxicity at the preceding dose level was acceptable. Unacceptable toxicity was defined as an elevation of the serum creatinine level to greater than 5 mg/dL, an elevation of the serum bilirubin level to greater than 5 mg/dL, dyspnea at rest, hypotension refractory to pressors, altered mental status, or other toxicities of grade 3 to 4, using the National Cancer Institute (NCI) Common Toxicity Criteria. The doses of rIL-2 administered were 4.0 x 10(6), 6.0 x 10(6), 8.0 x 10(6), 10.0 x 10(6), 12.0 x 10(6), 14.0 x 10(6), 18.0 x 10(6), 22.0 x 10(6), and 26.0 x 10(6) BRMP (Hoffman-LaRoche) U/m2. At a dose of rIL-2 10.0 x 10(6) BRMP U/m2, patients were also treated with doses of rHuIFN alpha 2a of 1.0 x 10(6) and 0.1 x 10(6) U/m2. RESULTS: A total of 57 patients were treated. Intolerable side effects (hypotension, pulmonary, and CNS toxicity) were produced by rIL-2 26.0 x 10(6) BRMP U/m2 and rHuIFN alpha 2a 10.0 x 10(6) U/m2. Two of 21 patients with renal cell carcinoma showed objective responses, and five of 17 patients with malignant melanoma responded. Two of these responses in melanoma were complete and continue to be longlasting. CONCLUSIONS: When given with rHuIFN alpha 2a 10.0 x 10(6) U/m2 as described above, the maximum-tolerated dose of rIL-2 is 22.0 x 10(6) BRMP U/m2. This dose of rIL-2 is equivalent to 50 to 60 MIU/m2, depending on the conversion factor used. Based on this experience and other trials, we favor phase II trials in renal cell carcinoma using an alternative dose schedule of this cytokine combination, in which rIL-2 is administered by continuous infusion. We suggest that phase II trials of this combination in patients with melanoma use an rIL-2 dose of 8.0 x 10(6) BRMP U/m2 by IV bolus injection three times weekly in combination with rHuIFN alpha 2a 10.0 x 10(6) U/m2 IM three times weekly.

Adult↗

PubMed1991

A Southwest Oncology Group phase II Trial of recombinant tumor necrosis factor in metastatic breast cancer.

New approaches are needed in the treatment of advanced breast cancer. In vitro studies have shown that recombinant tumor necrosis factor (TNF) is a growth inhibitor for the MCF-7, ZR-75-1, and BT-20 human breast cancer cell lines. Based on these considerations, the Southwest Oncology Group performed a Phase II trial of recombinant TNF (Genentech) (150 micrograms/m2) given by 30-minute intravenous infusion on days 1 to 5 of every other week for 8 weeks. Patients with metastatic breast cancer who had received one prior chemotherapy regimen for advanced disease were eligible. Of the 22 patients who were entered, 3 were ineligible. Nineteen patients who had a performance status of 2 or less could be examined (median age, 53 years). One possible fatal toxic reaction has been seen in a patient who had intracranial bleeding caused by a previously undiagnosed brain metastasis; no other treatment-related deaths have occurred. Toxicity has included nausea, vomiting, fever, chills, myalgia, and fatigue. No Grade 4 toxicity has been observed. Grade 3 toxic reactions have included hypotension (two patients), diarrhea (one patient), transient leukopenia (two patients), and reversible elevations of liver function test values (two patients). No objective responses have been observed. Twelve of 19 patients have died (median survival time, 8.5 months). Recombinant TNF is inactive as a single agent in patients with previously treated metastatic breast cancer.

Adult↗

PubMed1991

Clinical results and characterization of tumor-infiltrating lymphocytes with or without recombinant interleukin 2 in human metastatic renal cell carcinoma.

A Phase I trial of tumor-infiltrating lymphocytes (TIL) expanded in vitro and administered on Days 1 and 8, with or without continuous infusion recombinant interleukin 2 (rIL-2) in 25 patients with metastatic renal cell carcinoma, was conducted. Eighteen of the 25 eligible patients were treated with TIL and escalating doses of rIL-2 (0.0, 3.0, 4.5 x 10(6) units/m2) on Days 1 to 5 and 8 to 12. Dose-limiting toxicity was pulmonary, and the maximum tolerated dose of rIL-2 was 3.0 x 10(6) units/m2. No clinical responses were observed. Immunological monitoring of peripheral blood lymphocytes demonstrated significant increases in CD3+ and CD56+ cells, including the activated T-cell subsets. Phenotypic analysis of cultured TILs demonstrated significant heterogeneity and the presence of CD3+CD4+ and CD3+CD8+ T-cells, with CD3-CD56+ and CD3+CD56+ populations also present. The majority of cultured TILs expressed HLA-DR and CD45RO, with a variable number expressing CD25. The rIL-2-expanded TILs possessed cytotoxicity against allogeneic and autologous tumor, with cytolytic activity against only autologous tumor seen in one patient. Results demonstrate that in vitro expansion of TILs is possible, but further studies are needed to define the biology of TILs in renal cancer and to isolate and expand tumor-specific T-cells.

Adult↗