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PubMed1994

Combined immunochemotherapy (CEP, M-VEP + BCG) in the treatment of invasive bladder tumors.

Forty patients with invasive bladder tumors were consecutively treated and followed between June 1986 and February 1993. The treatment included systemic chemotherapy combining cyclophosphamide, epirubicin and cisplatin (CEP) or methotrexate, vinblastine, epirubicin and cisplatin (M-VEP) along with intravesically applied BCG vaccine. The treatment was well tolerated by the patients. No relevant toxic effects requiring hospitalization or fatalities due to the treatment were observed. Toxic manifestations of a hematologic nature were considerably less frequent than usual, nausea and vomiting being among the most frequently observed toxic signs on the second day of application of cisplatin. The side effects resulting from intravesically applied BCG vaccine showed no significant difference in terms of severity and variety from those due to its application in superficial tumors. A median follow-up of 50.3 months (range 6-80 months) showed an objective response to the treatment as follows: complete and partial response in 27 out of 40 (67.5%) and a complete clinical response in eight out of 40 (20%). Ten patients with partial response and stabilization had complete surgical response after operative treatment. The recurrence rate in patients with a complete response and a complete surgical response was 33% (six out of 18). The survival rate was 78% at 1 year, 70% at 2 years and 68% at 4 years. A complete response to the treatment of concomitant carcinoma in situ was observed in three patients. The lack of comparative and randomized studies and insufficient clinical experience did not allow an overall assessment of the therapeutic opportunities that our combined immunochemotherapy offers.(ABSTRACT TRUNCATED AT 250 WORDS)

Administration, Intravesical↗
PubMed1999

Sensitivity of short-term cultures derived from human malignant glioma to the anti-cancer drug temozolomide.

The activity of temozolomide, which has shown clinical activity against malignant glioma, has been assessed in vitro against short-term cultures derived from these tumors using an intermediate duration microtitration assay with MTT reduction as the end-point This assay has previously been shown to correlate closely with a monolayer clonogenic assay. Sensitivity was assessed in 15 short-term cultures (passage levels 3-9) derived from WHO grade III and IV astrocytomas. These cultures had a median ID50 value of 258 microM for temozolomide and 16.13 microM for CCNU. Maximum serum concentrations of temozolomide are of the order of 75 microM but only three of 15 (20%) cultures had ID50s below this value. Fourteen of 15 (93%) cultures displayed cross-resistance between temozolomide and CCNU, although one line which was extremely resistant to CCNU retained sensitivity to temozolomide. Comparative studies of published clonogenic survival curves indicate that the short-term glioma cell lines used in this study have similar sensitivities to established glioma cell lines, whilst colon carcinoma cell lines and bladder carcinoma are often more resistant to these drugs. Cell lines from testicular teratoma cell lines may show exquisite sensitivity to temozolomide and this level of sensitivity is seen only occasionally in short-term cultures derived from malignant glioma.

Adult↗
PubMed2003

Feasibility and toxicity of CCNU therapy in elderly patients with glioblastoma multiforme.

In our institution, 103 glioblastoma multiforme (GBM) patients aged from 55 to 83 years were treated since November 1994 as follows. All patients underwent surgical intervention (gross total resection, n = 35; subtotal resection, n = 38; stereotactic biopsy, n = 30). Subsequently all patients were offered radiotherapy and chemotherapy with CCNU. Results were as follows: 101 patients started radiotherapy, 93 patients completed it (96% of the patients aged < 65 years and 85% of the patients > or =65 years). All patients received at least 1 cycle of chemotherapy (median 3 cycles). Chemotherapy-associated toxicity was generally mild, more pronounced in females and did not increase with age. Median time to progression was 10.5+/-3.2 months for the patients < 65 years and 5.1+/-1 months for patients > or =65 years. median overall survival was 17.5+/-3.8 months in patients < 65 years and 8.6+/-1 months in patients > or =65 years (p < 0.0001). In multivariate analysis, age and female sex remained independent prognostic factors. Our data indicate that a treatment concept including concomitant radio- and chemotherapy is feasible even in elderly patients with GBM.

Aged↗
PubMed2003

Survival and prognostic factors of patients with unresectable glioblastoma multiforme.

The aim of this study was to assess survival and prognostic factors of 98 consecutive patients with unresectable glioblastoma multiforme (GBM) after stereotactic biopsy. Patients were diagnosed between 1993 and 1998, and the treatment modality subsequent to stereotactic biopsy was determined by the year of diagnosis. Before 1995, patients did not receive further specific therapy after stereotactic biopsy (n=36). In 1996, patients were administered radiotherapy starting within 6 weeks after stereotactic biopsy (n=24). From 1997 to 1998, patients received combined radio-/chemotherapy (RCT; CCNU orally) starting within 2 weeks after stereotactic biopsy (n=38). Patients' age ranged from 21 to 84 (median 64) years and their median Karnofsky performance score 2 weeks after stereotactic biopsy was 80 (range 60-100). Survival and prognostic factors were analyzed with respect to administered treatment modalities (without specific therapy versus radiotherapy versus combined RCT), with respect to age (>or or=or<80), tumor location (frontal, parieto-temporal, central, occipital) and tumor size (>or 5 cm) by the Kaplan-Meier method, by log-rank test and multivariate Cox regression analysis. Post-biopsy treatment modality was the strongest predictor for survival. Median (range) survival was 9 (3-47) weeks in those without specific therapy, 13 (5-54) weeks in patients receiving radiotherapy and 31 (11-101) weeks in patients receiving combined RCT (p<or=0.001). Age<or=50 years (p<or=0.05) in addition to tumor size in multivariate Cox analysis were found to be of significant influence onto survival, too. Combined RCT could be performed on a complete outpatient basis. Toxicity consisted of mild asymptomatic thrombocytopenia. We conclude that the administration of combined RCT within a minimum interval after stereotactic biopsy yielded a significant increase in survival. Patients' acceptance was excellent. These results encourage us to treat even patients with unresectable GBM with combined RCT.

Adult↗
PubMed1997

Tumor-infiltrating lymphocytes in patients with metastatic melanoma receiving chemoimmunotherapy.

Biopsies from 12 patients with progressive metastatic melanoma were excised during chemoimmunotherapy to evaluate and characterize the local immune response in situ in the metastases. These findings were compared with the distribution of lymphocyte subsets in the peripheral blood and correlated with the clinical data. The biopsy specimens were prepared for microscopic procedures, and the fields for analyses were chosen to involve a section of both stroma and the tumor area. The number of each lymphocyte subset was calculated and compared with the number of melanoma cells in the field, allowing quantitative characterization of the immune reaction in different samples. Comparison of the lymphocyte subsets of peripheral blood and metastatic lesions revealed equal relative amounts of CD4+ (helper) and CD8+ (suppressor/cytotoxic) cells in both tissues, but 10- to 20-fold fewer CD56+ (natural killer, NK) cells, and a total absence of CD20+ (B) cells in the metastatic lesions. The prognosis of patients was viewed at different stages of the disease. The median survival from the primary diagnosis of patients with a tumor CD4+/CD8+ ratio above the median was 4.4 years compared with 2.4 years for those with a ratio below the median (Logrank, p = 0.02). In the multivariate analysis, the only statistically significant prognostic factors were the CD4+/CD8+ ratio of the tumor (p = 0.010) and of the peripheral blood (p = 0.020). Monitoring of CD4+ and CD8+ cells may thus provide valuable information about the state of host defense, with a high CD4+/CD8+ ratio indicating more favorable prognosis.

Adult↗
PubMed2000

Quantitative 201Tl SPET imaging in the follow-up of treatment for brain tumour: a sensitive tool for the early identification of response to chemotherapy?

The aim of this study was to establish if repeated quantitative 201Tl SPET scanning during follow-up of astrocytoma therapy can provide information that is relevant for clinical management. Sixteen consecutive patients, with histopathologically verified highly malignant astrocytoma, were followed during PCV chemotherapy. Imaging with 201Tl SPET and CT was performed repeatedly over 8-16 weeks until treatment discontinuation, with a maximum follow-up of 74 weeks. Tumour uptake volume (TUV), a measure of metabolically active tumour tissue, was calculated from the SPET images. The reliability of early identification of treatment failure, defined as > 25% tumour volume increase, following one course (week 8) and three courses (week 24) of chemotherapy, was calculated for the two imaging methods. 201Tl SPET positive patients (> 25% tumour volume increase) were compared with 201Tl SPET negative patients in terms of time to treatment discontinuation (TTD) and survival time (ST). The patients were followed with a total of 59 SPET examinations, and treatment was continued for a median 27 weeks (range 16-78 weeks). The comparative reliability of SPET and CT showed the highest sensitivity and accuracy for SPET in the early identification of astrocytoma treatment failure at the week 24 assessment. Patients with positive 201Tl SPET after three courses of chemotherapy had a significantly reduced TTD (P = 0.040) but not significantly reduced ST. Of the ten patients who received concomitant radiation and chemotherapy, five had a small (0-10 ml) TUV at the week 24 assessment. Patients with a TUV > 10 ml at this assessment had a shorter TTD (P = 0.016) and a reduced ST (P = 0.024) compared to patients with a TUV < 10 ml. In conclusion, the assessment of progressive disease by quantitative 201Tl SPET appears to provide information on treatment response, earlier and with a higher reliability than CT. Repeated 201Tl SPET scanning during follow-up of astrocytoma treatment is an alternative tool for the early identification of treatment failure.

Adult↗
PubMed1996

Chemosensitivity of human melanoma metastases in mouse subrenal capsule assay--can it predict tumour response to combined cytostatic plus interferon therapy in metastatic melanoma?

We have analysed the chemosensitivity of 121 human melanoma metastases in the 6-day mouse subrenal capsule assay (SRCA). A total of 13 different chemotherapy regimens were analysed in four successive series. By the original criteria of the assay, 75% of tumours were sensitive to at least one regimen. The most effective combinations, giving sensitivity rates > 40%, were of dacarbazine, vincristine, and BCNU (DOB) with or without metronidazole, followed by cisplatin plus etoposide (Plat-VP16) combined with interferon. On the basis of the SRCA screening we developed a four-drug chemotherapy regimen combined with interferon for metastatic melanoma. Retrospectively analysed the assay correctly identified 77% of clinical responders and 54% of clinical non-responders. The overall predictive accuracy was 65%. Despite the limitations of the assay, it can be used for screening new drugs or combinations.

Animals↗
PubMedDate not supplied

Current chemotherapy for glioblastoma.

INTRODUCTION: Glioblastoma multiforme continues to be associated with a dismal prognosis, despite aggressive therapy. What limited therapeutic impact that has been made has come via multimodality treatment in which chemotherapy plays an important role. In this manuscript, we review current chemotherapy options for glioblastomas. METHODS: The current literature concerning glioblastoma multiforme chemotherapy was reviewed. In addition to a review of landmark references, a MEDLINE search of the literature published from January 2000 to November 2002 was performed using the key words "chemotherapy AND malignant glioma" and limiting responses to clinical trials. RESULTS: Several cytotoxic chemotherapeutic agents that are efficacious in treating glioblastoma are in common clinical use. These can be classified as first-line or second-line agents, depending on their efficacy. In addition, cytostatic chemotherapy agents are beginning to play a role in glioblastoma treatment. Finally, new methods to deliver high chemotherapy doses to brain tumors hold promise for future therapies. CONCLUSIONS: Despite the overall poor prognosis of patients with glioblastoma multiforme, multimodality treatment and chemotherapy in particular improve outcome, and chemotherapeutic options are beginning to have an increased impact. Strategies currently in clinical trials may improve this impact more in the future.

Antineoplastic Agents↗
PubMed1978

Combination chemotherapy in the management of superior vena caval obstruction in small-cell anaplastic carcinoma of the lung.

Among 225 consecutive patients with small-cell anaplastic bronchogenic carcinoma, 26 (11.5%) had superior vena caval obstruction when the malignancy was diagnosed. Of these 26 patients, a consecutive series of 22 were treated initially with combination chemotherapy (cyclophosphamide, methotrexate and CCNU, in some cases combined with vincristine) alone, and in all these cases resolution of the syndrome was prompt within a median of 7 days. In no case were symptoms increased transiently by the treatment. No difference in response rate was observed between the histologic subtypes of small-cell anaplastic bronchogenic carcinoma according to the WHO classification. Combination chemotherapy alone is an effective treatment of superior vena caval obstruction in patients with small-cell anaplastic bronchogenic carcinoma.

Aged↗
PubMed1992

Potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea's toxicity in vitro by two new bioreductive agents.

Two new bioreductive compounds, 9-[3-(2-nitro-1-imidazolyl)propylamino]acridine hydrochloride (NLA-1) and 9-[2-(2-nitro-1-imidazolyl)ethylamino]acridine hydrochloride (NLA-2), which behave as hypoxic cytotoxins and radiosensitizers, have been investigated for potentiation of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea's (CCNU) cytotoxic activity in vitro using V-79 cells. The preincubation effect as well as conditions of coadministration of CCNU with each sensitizer have been examined. In this latter case, the median-effect analysis was applied to evaluate whether the phenomenon was additive or synergistic. A clonogenic assay was used to score survival. Both bioreductive compounds, even at very low concentrations, significantly enhance the cytotoxic activity of CCNU under conditions of hypoxic preincubation. The enhancement of CCNU cytotoxicity is dependent upon preincubation time and the concentrations of both CCNU and the specific bioreductive agent. Coincubation of cells under hypoxia with CCNU and each bioreductive agent led to some potentiation, but only at lower survival levels. No chemosensitization was observed under aerobic conditions with either sensitizer.

Aminoacridines↗
PubMed1978

The proliferative state of clonogenic cells in the Lewis lung tumour after treatment with cytotoxic agents.

The proportion of clonogenic cells from the Lewis lung carcinoma which are in S-phase of the cell cycle has been measured as the fraction killed by a short exposure to hydroxyurea in vitro. Estimates of the proportions of S-phase cells before and 30 min after doses of gamma-radiation of 1000--2000 rad suggest no alternation in the cell cycle age distribution due to these doses of radiation. As the survivors of these high doses of radiation are predominantly hypoxic, the results imply that hypoxic cells have the same cell cycle age distribution as oxygenated cells in Lewis lung tumours. After treatment with cyclophosphamide or CCNU, the proportion of S-phase cells among the survivors exceeds the faction of S-phase cells in untreated populations. This increase is consistent with a relative resistance of S-phase cells to alkylating agents and nitrosoureas.

Animals↗
PubMed1979

A simple method for producing different growth fractions in vitro for use in anti-cancer drug studies.

A simple technique has been used experimentally to produce in vitro Chinese hamster ovary cells with growth fractions ranging from 0 to 100%. Known numbers of exponentially growing and plateau-phase tissue culture cells were mixed in various proportions to yield the desired final growth fraction. Cells attach to the culture flask surface within 1 hr of mixing. Treatment at that time with the nitrosourea compounds, CCNU and MeCCNU, resulted in differential drug survival sensitivities that were dependent upon the growth fraction of the population treated.

Animals↗
PubMed1983

Hypertrophic pulmonary osteoarthropathy: response to chemotherapy without documented tumour response.

A case is reported of severe hypertrophic pulmonary osteoarthropathy associated with bronchogenic carcinoma which successfully responded to chemotherapy, despite the fact there was no objective response in the primary lesion. Previous treatment and responses are briefly reviewed. The method or methods by which chemotherapy may alleviate HPOA in the absence of response to the primary lesion are discussed. The marked discrepancy between progression of the HPOA and progression of the clubbing is noted. The fact that HPOA is potentially treatable despite the prognosis of the primary is emphasised.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1991

Cisplatin combination chemotherapy for elderly patients with urothelial tumours.

The proportion of cancer patients who receive potentially curative therapy declines with increasing chronological age. Between January 1979 and January 1988, 36 patients aged from 76 to 84 years (median 78) consented to cisplatin combination chemotherapy. Eighteen patients received 1 to 7 cycles of adjuvant chemotherapy (median 5). This resulted in a drop in creatinine clearance rate from 70 +/- 28.5 ml/min to 49 +/- 20 ml/min. Eight patients (44%) are alive without evidence of disease, with a whole group median survival of 23 months. The dose intensity of cisplatin was found to predict recurrence. Eighteen other patients were treated for metastatic disease; 39% had an objective response after receiving 2 to 9 cycles (median 7). Only 2 patients (11%) are alive and free of disease. In this group no significant kidney damage occurred and the dose intensity of cisplatin did not predict response. Treatment resulted in a significant sepsis rate (39%) and 6 patients (17%) withdrew from treatment because of toxicity. It was concluded that cisplatin combination chemotherapy can be administered without treatment-related death and its efficacy is similar to that in younger patients. Age should not exclude patients from the potential benefit of such therapy. An important cause of reduced benefit from chemotherapy among elderly patients may be the reduced dosage of cisplatin.

Aged↗
PubMed1986

In vitro analysis of BCNU-sensitivity in human malignant gliomas. II. Cross-resistance studies with cisplatinum and nitrosoureas.

With the use of the Human Brain Tumor Stem Cell Assay (HBTSCA) in a cross-resistance study, four early (3-4) culture passages of human malignant gliomas (glioblastoma multiforme) were tested for in vitro chemosensitivity with three of the most effective single agents for brain tumor chemotherapy: BCNU, CCNU and cisplatinum (DDP). The shapes of the dose-response curves indicated complete cross-resistance between BCNU and CCNU, i.e. two chloroethyl-nitrosoureas sharing a common alkylating-carbamoylating activity, with no evident cross-resistance between the two nitrosoureas and the DDP, a DNA binder with a putatively different antitumor action. Probably because of differences in drug delivery kinetics or in the cytotoxic mechanism, DDP might play a role in the treatment of nitrosourea-resistant gliomas.

Brain Neoplasms↗