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PubMed2002

An elevated serum beta-2-microglobulin level is an adverse prognostic factor for overall survival in patients with early-stage Hodgkin disease.

BACKGROUND: The relative importance of prognostic factors in patients with early-stage Hodgkin disease remains controversial. The purpose of this study was to evaluate prognostic factors among patients who received chemotherapy before radiotherapy. METHODS: From 1987 to 1995, 217 consecutive patients ranging in age from 16 to 88 years (median, 28 years) with Ann Arbor Stage I (n = 55) or II (n = 162) Hodgkin disease underwent chemotherapy before radiotherapy at a single center. Most were treated on prospective studies. Patients received a median of three cycles of induction chemotherapy. Mitoxantrone, vincristine, vinblastine, and prednisone (NOVP), doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), mechlorethamine, vincristine, procarbazine, and prednisone (MOPP), cyclophosphamide, vinblastine, procarbazine, prednisone, doxorubicin, bleomycin, dacarbazine, and CCNU (CVPP/ABDIC), or other chemotherapeutic regimens were given to 160, 18, 15, 10, and 14 patients, respectively. The median radiotherapy dose was 40 Gy. Serum beta-2-microglobulin (beta-2M) levels ranged from 1.0 to 4.1 mg/L (median, 1.7 mg/L; upper limit of normal, 2.0 mg/L). We studied univariate and multivariate associations between survival and the following clinical features: serum beta-2M level above 1.25 times the upper limit of normal (n = 12), male gender (n = 113), hypoalbuminemia (n = 11), and bulky mediastinal disease (n = 94). RESULTS: Follow-up of surviving patients ranged from 0.9 to 13.4 years (median, 6.6 years) and 92% were observed for 3.0 or more years. Nineteen patients have died. Only elevation of the serum beta-2M level was an independent adverse prognostic factor for overall survival (P = 0.0009). CONCLUSIONS: The prognostic significance of a simple, widely available, and inexpensive blood test, beta-2M, has not been studied routinely in patients with Hodgkin disease and should be tested prospectively in large, cooperative group trials.

Adolescent↗
PubMed1976

Combination chemotherapy of adult acute lymphocytic leukemia.

Seventeen adults with previously untreated acute lymphocytic leukemia (ALL) received thioguanine, vincristine, dexamethasone, and pyrimethamine for remission induction. Nine patients (53%) achieved complete and 5 (30%) partial remissions. Once in complete remission patients were given two closely separated consolidation courses followed by monthly maintenance courses of the same regimen with the addition of 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU) every other month during maintenance therapy. The median duration of complete remission was 176 days (range 38 to 605). The median survival for all patients was 405 days (range 30 to 1,058+). Oral pyrimethamine and CCNU were used for their potential activity as prophylactics against meningeal leukemia. Dexamethasone was used instead of prednisone because of the potential enhancement of granulocyte mobilization by the former. Six patients (35%) developed meningeal leukemia while on initial induction or maintenance therapy, 5 within 6 months of diagnosis. Life-threatening infections occured in 10 patients (59%) during induction. Whereas the regimen effectively induced complete remission in about half of previously untreated adults with ALL, it was not effective in maintenance. The incidence of meningeal leukemia and infection during induction was high. Oral pyrimethamine was inadequate prophylaxis for meningeal leukemia; dexamethasone did not reduce the incidence of serious infection.

Adolescent↗
PubMed1988

Sister chromatid exchange induction near the baseline with low doses of the alkylating agent CCNU.

Sister chromatid exchange (SCE) and cell-cycle kinetics were examined at near-baseline levels in human peripheral lymphocytes exposed to low doses of the potent SCE inducer 1-(2-chloroethyl)-3-cyclohexyl-1-nitrosourea (CCNU), in vitro. A preliminary SCE dose-response curve was determined with a broad range of doses of CCNU using a single donor. SCE induction was approximately linear over the entire dose range from 5 to 200 microM CCNU. Cell cycle kinetics were retarded in a dose-dependent manner. A second dose-response curve from the same donor was constructed using several doses of CCNU between 0.5 and 10 microM to evaluate linearity and uniformity of SCE response near baseline levels. SCE induction was approximately linear between 1.0 and 10.0 microM CCNU. Finally, SCE and cell-cycle kinetics were examined in 12 donors at doses of 1.0, 5.0, and 10.0 microM CCNU to evaluate the reproducibility of near-baseline SCE induction over a range of subjects. Cell-cycle kinetics were retarded at all three doses with a highly significant increase in SCE frequencies at 5.0 and 10.0 microM CCNU. These data suggest that increases in SCE less than twice background can be reliable indicators of genotoxic exposure.

Cell Cycle↗
PubMedDate not supplied

Osteonecrosis of the jaws: a complication of cancer chemotherapy.

Two unusual cases of osteonecrosis of the jaws in edentulous patients are described. One case involved the maxilla and the other the mandible. Both patients were compromised hosts who were undergoing cancer chemotherapy. Both developed local mucosal infections beneath their dentures before the bone became involved. The role of dentures in producing local irritation and in masking the problem is discussed.

Adult↗
PubMedDate not supplied

The management of early-stage aggressive non-Hodgkin's lymphoma.

Sixty-one patients with stage I or II non-Hodgkin's lymphoma of aggressive histological subtype were treated at the Royal Marsden Hospital between 1972 and 1984. The overall 5-year survival probability was 69 per cent (60 per cent continuously relapse-free). The 5-year survival probability was 80 per cent for stage I disease and 55 per cent in stage II (p = 0.05). Survival was significantly higher in non-bulky than bulky presentations (85 per cent versus 44 per cent at 5 years, p = 0.003). There was no significant 2-year survival difference between those treated initially with chemotherapy and those treated with radiotherapy alone (65 per cent versus 83 per cent), however chemotherapy had been employed predominantly in patients with adverse presentations. The 2-year survival in 41 patients treated initially with doxorubicin-containing chemotherapy combinations was 76 per cent. Combined modality treatments should be considered especially in patients with stage II or bulky disease.

Antineoplastic Combined Chemotherapy Protocols↗
PubMedDate not supplied

Salvage chemotherapy for non Hodgkin's lymphoma of unfavourable histology with a combination of CCNU and vinblastine.

Twenty patients with relapsed or refractory, intermediate or high grade non Hodgkin's lymphoma were treated with a combination of CCNU and vinblastine. Complete responses occurred in four patients (20 per cent), partial responses in eight (40 per cent), for an overall response rate of 60 per cent. The regimen was more effective in patients with high grade lymphoma, absence of constitutional symptoms, better response to prior treatment. Duration of response was 4, 8, 16, 30 months for complete responders; 2, 2, 6, 6, 6, 8, 9, 14 months for partial responders. This combination regimen seems at least as effective as most of other regimens utilized in salvage treatment of non Hodgkin's lymphomas, with a very acceptable toxicity.

Adult↗
PubMed2002

High expression levels of collagenase-1 and stromelysin-1 correlate with shorter disease-free survival in human metastatic melanoma.

Matrix metalloproteinases (MMPs) are proteolytic enzymes capable of degrading extracellular matrix. Their role has been emphasized in tumor invasion, metastasis and tumor-induced angiogenesis. We studied the expression of collagenase-1 (MMP-1), stromelysin-1 (MMP-3) and collagenase-3 (MMP-13) in 70 melanoma metastases obtained from 56 patients treated with combined chemoimmunotherapy. The patients were divided into 2 groups using a cut-off point of 0% for MMP-1 expression and 20% for MMP-3 expression. We found that patients with MMP-1 positive metastases (n = 38) had significantly shorter disease-free survival compared to patients with MMP-1 negative metastases (n = 18) (median 11.2 vs. 17.0 months, p = 0.0383). The disease-free survival of patients with high levels of MMP-3 expression in their metastases (> or = 20% positive tumor cells, n = 14) was also significantly shorter compared to patients with lower levels of expression (n = 42) (median 5.1 vs. 14.0 months, p = 0.0294). The expression of MMP-13 did not correlate to survival parameters. We also found that the presence of melanin, a pigment produced by melanocytes, correlated with high expression levels of MMP-1 (p = 0.0002), MMP-3 (p < 0.0001) and MMP-13 (p = 0.0009). The high expression levels of MMP-13 were also associated with the presence of visceral metastases (p = 0.0284). Our findings suggest that MMP-1 and -3 may have a special role in melanoma metastasis formation and thus they could be used to measure the biological activity of the disease.

Adult↗
PubMed1980

Response to chemotherapy of human, malignant melanoma xenografts in athymic, nude mice.

In attempts to elucidate the factors determining individual differences in response of tumors to chemotherapeutic agents, the sensitivity of six human malignant melanomas growing in athymic, nude mice was studied. Six agents, viz. DTIC, CCNU, vinblastine, procarbazine, as well as the toxic lectins abrin and ricin, were administered in maximum tolerable doses to the tumor-bearing mice. The response to treatment was expressed as tumor growth delay, i.e. the number of volume double times saved by the treatment. The xenografts had very nearly retined the morphology of the parent tumors and were histologically similar. They showed different and characteristic early growth rates and also wide variations in their response to the agents tested. Unexpectedly, in the case of DTIC, CCNU and procarbazine, the response of the xenografts proved to be inversely related to the early growth rates of the tumors. For vinblastine, abrin and ricin, no correlation between response and growth rate of the tumors was apparent. Procarbazine had the best overall effect among the agents here tested. DTIC, CCNU and vinblastine had somewhat less and about equal overall efficiency. The plant toxin abrin, which acts by inhibiting protein synthesis, was at least as effective as DTIC. When abrin was given together with DTIC, the effect on the two xenografts tested was superior to that of each agent given alone. The wide variations observed in the response of the histologically similar xenografts to the different agents demonstrate that testing of the chemosensitivity of human xenografts requires the use of a panel of tumors of each histological tpye. The clear relationship found between the early growth rate of the xenografts and their sensitivity to three of the drugs most commonly used in the treatment of malignant melanomas, may have clinical implications.

Abrin↗
PubMed1981

Cultivation of human melanomas in soft agar. Factors influencing plating efficiency and chemosensitivity.

As part of a programme to study the predictive clinical value of a soft agar assay for measuring chemosensitivity of human melanomas in vitro, we have observed the effect of three disaggregation methods on the yield of tumor cells, plating efficiency in soft agar and chemosensitivity. The yields and plating efficiencies obtained, as well as sensitivity to DTIC, CCNU, vinblastine and abrin, were about the same whether collagenase/pronase/DNase-treatment, trypsin/EDTA-treatment or mechanical treatment was used. When melanoma xenografts of different sizes were studied, an inverse relationship between tumor size and plating efficiency was found, whereas chemosensitivity was unaffected by tumor size. The highest plating efficiencies of melanoma cells, both from patient biopsies and from xenografts, were obtained when red blood cells were present and a low oxygen concentration (5%) was used. The results demonstrate that, in the case of melanomas, the fraction of tumor cells that are clonogenic in vitro depends on the size of the tumors, and even more so on the culture conditions used. An important finding was that chemosensitivity in vitro appears to be unaffected by the disaggregation method and by tumor size.

Abrin↗
PubMed1985

The relationship between tumour geometry and the response of tumour cells to cytotoxic drugs--an in vitro study using EMT6 multicellular spheroids.

Multicellular spheroids of the EMT6/Ca/VJAC mouse mammary tumour cell line have been used in an investigation of the effect of tumour geometry on the response of tumour cells to 3 cytotoxic drugs, adriamycin (ADM), nitrogen mustard (HN2) and CCNU. In addition to the inherent cellular drug response, factors related to spheroid structure, namely cell-cycle distribution, intercellular contact, drug penetration and microenvironment (pH, oxygen, glucose, etc.) are believed to influence the response of cells within spheroids to cytotoxic drugs. Selective enzymatic dissociation (with bacterial neutral protease) has been used to separate the cells within large (approximately 800 micron in diameter) spheroids into 4 distinct subpopulations. The cells within the subpopulations have been characterized by their DNA content, RNA content, tritiated thymidine labelling index, cell size and clonogenic capacity. It was found that cells at the surface of spheroids are relatively larger and more proliferative than cells towards the centre while their clonogenic capacity is similar. Studies on the responses of EMT6/Ca/VJAC log and plateau-phase monolayer cells have been carried out in parallel and have shown that cycling cells are more sensitive to ADM and HN2 than are non-cycling cells but somewhat less sensitive for the response to CCNU. Since the response patterns of cells from different regions of spheroids to HN2, treated either before disaggregation (intact spheroid) or after disaggregation (isolated spheroid cells), are similar and the surviving fraction increases from the surface towards the centre of the spheroid, cell cycle distribution is thought to be the only factor involved in the cytotoxicity of HN2 towards cells within the spheroids. Although the patterns of response to ADM of cells within intact spheroids and isolated spheroid cells are similar to those for HN2, the initial slope of the curve for intact spheroids is much steeper than that of the isolated spheroid cells. Therefore, in addition to the factor of cell-cycle distribution, drug penetration also appears to be involved in the action of ADM on spheroids, while the factors of intercellular contact and microenvironment appear to be relatively less important. The reverse pattern was found for the response of cells within different regions of spheroids to CCNU, treated as intact spheroids or as isolated spheroid cells (i.e., greater killing of inner compared with outer cells).(ABSTRACT TRUNCATED AT 400 WORDS)

Animals↗
PubMed1986

Effect of Fluosol-DA/O2 on tumor-cell and bone-marrow cytotoxicity of nitrosoureas in mice bearing FSA-II fibrosarcoma.

The perfluorochemical emulsion, Fluosol-DA, combined with carbogen breathing, potentiates the effects of radiation and a number of chemotherapeutic agents in several rodent tumors. The interaction of Fluosol-DA with drugs may be quite complex. In addition to increasing the oxygen supply in the tumor, Fluosol-DA may alter the pharmacokinetics of the drug and function as a drug delivery system. A series of 4 nitrosoureas of varying lipophilicity were administered as single doses intravenously (i.v.) to C3H/Be/FeJ mice bearing subcutaneous FSa-IIC fibrosarcomas. Doses of 40 mg/kg of CCNU, 15 mg/kg of BCNU, 20 mg/kg of MeCCNU and 15 mg/kg of chlorozoticin followed by 2 hr of breathing 95% oxygen produced tumor growth delays of 7.5, 4.0, 3.8 and 2.7 days, respectively. When the drug injection was followed immediately by 0.3 ml of Fluosol-DA and 2 hr of breathing 95% oxygen, the tumor growth delay produced by CCNU, BCNU, MeCCNU and chlorozoticin increased 2-fold, 10-fold, 4.5-fold and 3.5-fold, respectively. Administration of the drugs in Fluosol-DA followed by 2 hr of 95% oxygen breathing resulted in a 3.5-fold increase in tumor growth delay with CCNU, a 17-fold increase with BCNU, a 12.5-fold increase with MeCCNU and a 6-fold increase with chlorozoticin compared to drug and 95% oxygen breathing. These results are quantified in terms of cell survival by the tumor excision assay. Effects on the bone marrow from each treatment were measured using the granulocyte-monocyte colony-forming units (CFU-GM) assay. There was no correlation between the lipophilicity of the nitrosoureas tested and the tumor growth delay produced by each treatment.

Animals↗
PubMed1991

Hodgkin's disease in adults in Saudi Arabia. Clinical features, prognostic factors and an analysis of therapy. Outcome of combination chemotherapy only, for both localized and advanced disease.

Fifty evaluable, previously untreated, adult patients with clinically staged (CS) early and advanced Hodgkin's disease were treated with chemotherapy alone, using various regimens. Their mean age was 31.9 years. Fifteen patients (30%) had CS I or II and 35 (70%) had CS III or IV. Eighty-eight per cent of patients had one or more of the B symptoms and 64% had an unfavorable histology. Complete remission (CR) was achieved in 43 out of 50 patients (86% with 95% confidence interval of 76% to 96%), partial remission in 3 (6%) and treatment failure in 4. Adjusted analysis, using all possible subset regression, showed that unfavorable histology, bulky disease and receiving a total dose-intensity (TDI) less than or equal to 0.80 were negatively associated with the likelihood of achieving CR. At a median follow-up of 36 months (range, 6-90), 84% of patients were alive and 82% were disease-free. The overall median survival has not been reached, but the projected 5-year survival probability was 79%. Time-to-relapse was also estimated for those who achieved initial CR. The estimated 5-year relapse-free survival was 87%. The Cox proportional hazards model predicted that unfavorable histology, bulky disease and TDI less than or equal to 0.80 had an independent, adverse influence on survival. We conclude that the results of chemotherapy alone are encouraging and the rationale is practical and acceptable in those countries where the availability of radiotherapy units is limited.

Adult↗
PubMed1996

Correlation of in vitro drug sensitivity testing results with response to chemotherapy and survival: comparison of non-small cell lung cancer and small cell lung cancer.

Clinical protocols for small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC) were devised to prospectively select individualized chemotherapy based on in vitro drug sensitivity testing (DST) of cell lines derived from the patient's SCLC tumor cell lines or the patient's fresh NSCLC tumor. DST data derived from SCLC tumor cell lines were available for 33/115 (29%) patients. The DST-selected chemotherapy regimen was administered to 21 (18%) patients, or 64% of patients with DST. In SCLC< the DST-selected chemotherapy was administered either during weeks 13-24 following 12 weeks of etoposide/cisplatin, or at relapse after complete response to etoposide/cisplatin. Several parameters of in vitro drug sensitivity were significantly associated (two-sided P < 0.05) with clinical response to primary therapy and also with response to the DST-selected chemotherapy regimen, but were not associated with survival (P = 0.24). Five patients treated with their DST-selected chemotherapy attained a complete or partial response, compared to 5 of 68 who received an empiric regimen (P = 0.057). A total of 36/165 (22%) NSCLC patients had DST successfully completed. These results directed management for 21/96 (22%) patients who eventually received chemotherapy, or 58% of patients with DST. Response to chemotherapy for the patients treated prospectively with their DST-selected chemotherapy regimen (2/21; 9%) was not significantly different than the response rate for patients treated empirically with etoposide/cisplatin (10/69; 14%) in the absence of in vitro results to direct chemotherapy (P = 0.73). There was no difference in survival by treatment group for the NSCLC patients. The correlation between in vitro and clinical response was not significant for any individual drug or for all drugs considered together, illustrating the poor predictive value of in vitro testing with currently available chemotherapy in NSCLC.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1975

A clinical trial of CCNU (1-(2 chloroethyl)-3-cyclohexyl-1-nitrosourea) (NSC 79037) in advanced ovarian carcinoma.

CCNU is a useful drug in treating advanced ovarian carcinoma. Of patients with advanced ovarian carcinoma 37% responded favorably to CCNU. Thrombocytopenia was the primary toxic reaction. Clinical trials are in progress to compare the relative effectiveness, the degree of cross-resistance, and the difference in toxicity between CCNU and alkylating agents.

Alkylating Agents↗
PubMed1976

A randomized pilot study comparing two regimens in the treatment of squamous cell carcinoma.

Thirty-five patients with epithelial carcinomas not considered to be surgically resectable were randomized to receive two different chemotherapy regimens. Regimen 1 was CCNU followed by bleomycin, and Regimen 2 was a combination of CCNU, bleomycin, methotrexate, and vinblastine. Five of 14 patients treated with CCNU-bleomycin had partial responses. Three of 15 patients treated with the four-drug combination had a partial response. The toxicity of the four-drug regimen was significantly greater than that of the two-drug regimen, while the response rate was greater among those patients treated with two drugs. No significant clinical infections occurred despite the fact that leukopenia and thrombocytopenia were more severe and frequent with the four-drug regimen. Most importantly, the two-drug regimen is well tolerated as an outpatient procedure. Two of the two-drug and one of the four-drug recipients were converted from an inoperable to an operable state. In view of the fact that there has not heretofore been an effective chemotherapeutic regimen for Stage III and IV squamous carcinoma, this is a significant observation. It is of note that patients with squamous cell carcinoma of the head and neck were those who responded best to this treatment, although the treatment is worthy of consideration for advanced squamous carcinoma in other areas.

Bleomycin↗
PubMed1977

Current status of the therapy of advanced renal carcinoma.

A preclinical murine renal model system is available for evaluation of the effectiveness of therapeutic agents. Clinical review reveals that objective response rates to hormonal agents reported since 1971 have been substantially lower than those reported prior to 1971. Many chemotherapeutic agents have not been adequately evaluated clinically or with the experimental model. Vinblastine to date may be the most active single agent with a 25% objective response rate. At the present time, it is uncertain whether combination chemotherapy or hormonal chemotherapy add to response rates obtained with single agents. There is some evidence that immunotherapy may be of some adjuvant benefit and, thus may provide an additional avenue of investigation.

Adenocarcinoma↗
PubMed1978

Adriamycin, bleomycin, and CCNU as effective induction chemotherapeutic agents in advanced squamous cell carcinoma (COG Protocol 7333).

Twenty-six member institutions of the Central Oncology Group entered 154 patients in this two-armed, phase III study comparing the effects of adriamycin, bleomycin, and CCNU against a variety of squamous cell carcinomas. The combination of adriamycin and bleomycin produced a 43% overall response rate in primary tumors of the head and neck, which included two complete responses. This compares favorably to the results obtained with methotrexate and other agents previously reported. The combination of adriamycin and bleomycin will probably be the most useful for induction chemotherapy because both drugs have cumulative toxicities and the duration of response to this combination is short.

Aged↗