[Progress of treatment on lung cancer--US-Japan joint seminar].
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Carcinoma, Non-Small-Cell Lung↗
Biomedical subjects
Y Ariyoshi
Publications and source records attributed to Y Ariyoshi.
Serum glutathione S-transferase-pi level as a tumor marker for non-small cell lung cancer. Potential predictive value in chemotherapeutic response.
BACKGROUND: Resistance to chemotherapeutic agents is a major problem in non-small cell lung cancer (NSCLC) chemotherapy, and recent studies have indicated that glutathione S-transferase-pi (GST-pi) may play an important role in the resistance of cancer cells to alkylating agents that include platinum compound. METHODS: GST-pi in serum of 121 patients with NSCLC was measured by a sandwich enzyme-linked immunosorbent assay, and the serum concentrations of carcinoembryonic antigen (CEA), squamous cell carcinoma (SCC) antigen, and neuron-specific enolase (NSE) were also examined. Serum levels of these tumor markers were also evaluated in relation to therapeutic response in 69 patients who received combination chemotherapy with platinum compound. RESULTS: Fifty of 121 patients with NSCLC (41.3%) showed elevated serum GST-pi levels above a cutoff value of 34.8 ng/ml (mean + two standard deviations in 30 healthy control subjects). The positive rate of GST-pi in patients with NSCLC was higher than those of CEA (37.2%), SCC (15.7%), and NSE (14.9%). The mean pretreatment GST-pi level was significantly lower in patients with a partial response to chemotherapy than in those with no response (26.9 +/- 11.3 ng/ml versus 38.8 +/- 16.7 ng/ml; P < 0.003). Among patients with elevated levels of pretreatment serum GST-pi, only 13.8% (four of 29) responded to the combination chemotherapy, whereas partial response was observed in 40.0% of patients (16 of 40) with serum GST-pi concentration below the cutoff level (P < 0.02). Neither CEA, SCC, nor NSE showed such a relationship. CONCLUSIONS: The serum GST-pi level may have limited value as a tumor marker for NSCLC: Interestingly, pretreatment serum GST-pi levels may be a useful parameter for predicting therapeutic response to combination chemotherapy regimens that include platinum compound.
Adult↗
Ectopic expression of c-kit in small-cell lung cancer.
Accumulating evidence suggests that c-kit plays an important role in the regulation of growth of at least 3 lineages of stem cells, while only very limited data are available on the development of human solid tumors. Our recent studies have shown that c-kit transcripts are expressed in a very restricted sub-set of human solid tumors such as small-cell lung cancer (SCLC). We have also conducted an immunohistological study on in situ localization of the c-kit protein in various human solid tumors as well as in corresponding fetal and adult normal tissues. No c-kit expression was detected in normal bronchial epithelial cells or pneumocytes in lung parenchyma of human fetal and adult specimens, indicating that the c-kit protein is aberrantly expressed in lung-cancer cells. We also found that significant chemotactic response as well as moderate in vitro cell growth occurred in SCLC cell lines upon addition of recombinant human stem-cell factor.
Adenocarcinoma↗
Hepatic arterial infusion chemotherapy for liver metastases from breast cancer.
Between 1985 and 1992, 56 patients with unresectable liver metastases from breast cancer were treated by repeated hepatic arterial infusion chemotherapy employing an implantable port system. 5-Fluorouracil (5-FU) at 330 mg/m2 per week. Adriamycin (ADR) at 20 mg/m2 every 4 weeks, and mitomycin C (MMC) at 2.7 mg/m2 every 2 weeks were given to 42 patients. The remaining 14 patients received 5-FU at 330 mg/m2 per week and epirubicin (EPIR) at 20 mg/m2 every 2 weeks. As a rule, the treatment was performed on an outpatient basis. The side effects and complications observed included myelosuppression (41%), hepatic arterial occlusion (23%), and gastric mucositis (20%), but no major toxicity was encountered. The response rate (CR+PR) of the evaluated patients as determined from CT scans was 81%. The overall median survival period was 12.5 months. Only 14% of the patients died due to regrowth of liver metastases, and in 70% of the total cases, death due to liver metastases was avoided by this treatment. Thus, repeated hepatic arterial infusion chemotherapy for liver metastases from breast cancer might be capable of prolonging the survival of patients via avoidance of death due to the liver metastases.
Adult↗
Expression of CD44 variant isoforms in normal and neoplastic cells of the lung.
CD44 is a cell surface receptor that has been implicated in lymphocyte homing, hematopoiesis, cell migration and possibly also tumor metastasis. In the present study, expression of CD44 variant (CD44v) isoforms was analyzed in 23 lung cancer specimens together with corresponding normal lung tissues by Southern blot analysis coupled with reverse transcription-polymerase chain reaction amplification. We found that CD44v isoforms were expressed in all lung cancer specimens, suggesting a possible role in the establishment of metastases by these highly malignant tumors, but normal tissues were also positive. This is in marked contrast to the previous reports of essentially negligible expression of CD44v isoforms in normal colon and breast, and suggests a physiological function in the lung.
Base Sequence↗
Pamidronate treatment in patients with tumor-associated hypercalcemia: pharmacological effects and pharmacokinetics.
The purpose of this study was to investigate the effects of pamidronate, a second generation bisphosphonate, on the change in calcium homeostasis in patients with tumor-associated hypercalcemia. Eight patients with tumor-associated hypercalcemia received intravenous infusion of pamidronate (45 mg) and their high mean serum calcium concentration significantly decreased from 3.56 mmol/L to 2.62 mmol/L7 days after treatment. Serum intact PTH before treatment had been suppressed to below normal in all patients but returned to normal range in six patients within 7 days after treatment. Urinary PTH related peptide (PTHrP) excretion before treatment had been elevated in seven patients and then significantly increased further after pamidronate therapy. The serum bone Gla protein concentration was not apparently changed by the treatment. Pamidronate in serum was rapidly eliminated after the treatment and urinary excretion reached a plateau on the second day (13.8% of the administered dose), suggesting that the major portion of the infused dose had been distributed to the bone and other tissues. These findings suggest that pamidronate has a potent hypocalcemic effect and that PTHrP production in malignant tumors could be affected by pamidronate therapy.
Aged↗
[Phase I clinical trial of RP 56976 (docetaxel) a new anticancer drug].
A multicenter phase I clinical trial of RP 56976 (docetaxel), a new anticancer drug, was performed with single and repeated doses. Based on the results of phase I clinical trials conducted in the United States and Europe, the starting dose was 10 mg/m2. The dose was subsequently increased to 20, 50, 70 and 90 mg/m2. A dose of 60 mg/m2 was additionally tested. Single administrations of the six dose levels were performed in a total of 27 patients via intravenous drip infusion over one hour. Ten of the patients subsequently received repeated doses at three of the dose levels in the same manner. The dose limiting factor (DLF) of docetaxel is leukopenia (especially, neutropenia). Based on the observation of the DLF, the maximum tolerated dose (MTD) was determined to be 70-90 mg/m2. The white blood cell count reached a nadir about 9.5-19.5 days (median) after administration, and took 7-11 days (median) to recover. Other adverse reactions observed were nausea/vomiting anorexia, alopecia, diarrhea, fatigue and fever, which were all acceptable. The results of this trial suggest that a dosage regimen of 60 mg/m2 at 3- to 4 week intervals is appropriate in an early phase II clinical trial.
Adolescent↗
[The value of hepatic arterial infusion chemotherapy for liver metastases--discussion from viewpoints of prevention of hepatic death and QOL].
The value of hepatic arterial infusion chemotherapy for liver metastases was discussed from the viewpoints of the prevention of hepatic death and the negative effect on QOL, based on the results of repeated hepatic arterial infusion chemotherapy for 128 patients with unresectable liver metastases employing implantable catheter and port system. In 70% of patients, hepatic death due to metastases was prevented by this therapy, and the negative effect on QOL by this therapy was limited. Thus, in spite of the limited effects on the prolongation of survival compared with systemic chemotherapy, there is a reasonable basis for the use of hepatic arterial infusion chemotherapy as a treatment for unresectable liver metastases.
Antineoplastic Combined Chemotherapy Protocols↗
Concurrent cisplatin-etoposide chemotherapy plus thoracic radiotherapy for limited-stage small cell lung cancer. Japanese Lung Cancer Chemotherapy Group in Japanese Clinical Oncology Group.
A recent approach in the treatment of limited-stage small cell lung cancer (LDSCLC) has involved a combined modality of chemotherapy and chest irradiation. In using the modality, the study of scheduling methods for combining chemotherapy and radiotherapy should lead to other trials of combined modalities against LDSCLC since it is the most basic issue to be evaluated. We have thus conducted a multicenter phase II trial of concurrent cisplatin-etoposide (PVP) chemotherapy and radiotherapy for LDSCLC to determine the effects of the concurrent administration of a PVP regimen and chest irradiation on response rate, relapse, survival and treatment toxicity. The chemotherapy regimen consisted of a four-week cycle: cisplatin (80 mg/m2, given intravenously on day 1) and etoposide (100 mg/m2, given intravenously on days 1-3). This cycle was given four to six times within six months. Chest irradiation to the primary tumors at both the hili and the mediastinum was administered in standard fractions on days 2-12 in the first cycle of chemotherapy and on days 29-47 in the second cycle, with a total dose of 40-50 Gy. Prophylactic cranial irradiation was performed among complete remission (CR) or good partial remission (PR) patients after completion of the concurrent therapy. A total of 66 patients were entered into the trial and 59 were evaluated. The concurrent therapy induced an overall response rate of 94.9% in 59 patients: 24 patients, 40.7% CR, 32 patients, 54.2% PR. The median response duration was 8.7 months, and the median survival time for all eligible patients was 14.8 months. The percentage of patients with two-year survival periods was 20. A local relapse within the irradiated area was seen in only 22% of relapse patients. Brain metastases occurred in 24% of patients. Four of 32 patients treated with prophylactic cranial irradiation had brain metastases. Toxic effects, chiefly grades 3 and 4 leukopenia, as established by the World Health Organization, were detected in all treated patients. Other toxicities, including radiation-induced esophagitis and pneumonitis, were deemed almost acceptable. We concluded concurrent treatment of a PVP regimen with chest irradiation to be a feasible and beneficial therapy with an efficacy compatible to that of other published reports. The outcome of this protocol warrants further investigation to determine the optimal type of schedule for concurrent chemoradiotherapy against LDSCLC.
Adult↗
[New promising anticancer drugs for lung cancer].
New promising anticancer drugs for chemotherapy against lung cancer were reviewed on the basis of the outcomes of clinical trials which were carried out in Japan, USA and Europe. They included irinotecan, 254-S, vinorelubine, gemcitabine, taxol and Taxotere. Response rates of CPT-11 (irinotecan) were evaluated to be approximately 30% for non-small cell lung cancer (NSCLC) and more than 40% for small cell lung cancer (SCLC). Dose limiting toxicities was leukopenia and diarrhea. These toxicities should be managed very carefully because these occasionally might be life-threatening. Efficacy of 254-S, vinorelbine and gemcitabine were thought to be moderately active for NSCLC. Main toxicity was leukopenia and others were tolerable. Clinical trials of taxol and taxotere showed to be promising for NSCLC. Dose limiting factor was leukopenia. As for hypersensitivity seen in the administration of taxol, it is noted that premedication of antiallergic drugs is required. Taxol and Taxotere will be important for combined chemotherapy for advanced stage lung cancer.
Antimetabolites, Antineoplastic↗
[Clinical trials of new antitumor drugs in hematopoietic malignancies].
Although there is general agreement regarding the overall research goals of clinical trials of new antitumor drugs, there is a difference between the goal for chemotherapy sensitive tumors such as hematopoietic malignancies or germ cell tumors and the insensitive tumors such as most solid tumors. Hematopoietic malignancies like leukemia or malignant lymphoma are highly responsive to chemotherapy, approximately 70% of patients can reach complete remission, and some can survive for a long time. Furthermore, hematopoietic malignancies have a low incidence and the disease progresses rapidly. In this situation, clinical trials of new drugs for hematopoietic malignancies should be designed in the most efficient and ethically appropriate way. In this paper, we reviewed the recent clinical trials of new drugs for acute leukemia or malignant lymphoma. On the basis of these reviews, we proposed a frame-work that may improve the protocol design and address the ethical issues of phase studies for the development of new drugs for hematopoietic malignancies.
Acute Disease↗
[Dose intensity in cancer chemotherapy (including high dose chemotherapy)].
It has been difficult to compare the impact of different dosing practices in treatment programs. Hryniuk and colleagues retrospectively analyzed treatment outcome in a number of different tumors as a function of what they have termed dose intensity. They defined dose intensity as the amount of drug delivery per unit of time, expressed as mg/m2/wk, regardless of the schedule or route of administration. Relative dose intensity (RDI) is the amount of drug delivered per unit of time relative to an arbitrarily chosen standard single drug, or, for a combination regimen. Calculation of the dose intensity, therefore, require the assumption that differences in scheduling dose not influence treatment outcome. Retrospective reviews of the clinical literature indicate that dose intensity of single agent or combination chemotherapy correlates well with outcome in cancer of the breast, lung, ovary colon, or lymphoma. To confirm adequately the data obtained from retrospective review prospective randomized trials are required to determine whether dose (dose intensity) is independent determinant of outcome. In this paper prospective trials of dose intensity were reviewed and some of them in breast cancer, small cell lung cancer, ovarial cancer, malignant lymphoma, or germ cell tumor showed correlation between dose intensity and single anticancer agent regimens or combination regimens. High dose chemotherapy with supportive therapy such as administration of hematopoietic growth factor, autologous bone marrow transplantation, or peripheral blood stem cell transfusion, was also reviewed. Some of these modality showed the suggestive correlation between these therapeutic intensification and the prolongation of survival rate. Intensive chemotherapy for curable intent should be investigated very carefully in near future.
Antineoplastic Agents↗
[Phase-I clinical study of KW-2307 combined with cisplatin in non-small cell lung cancer patients].
A phase-I clinical study with coadministration of a new vinca alkaloid derivative KW-2307 with cisplatin (CDDP) at 80 mg/m2 to patients with non-small cell lung cancer was conducted by a collaborative study among 6 institutions. CDDP was given on day 1 and KW-2307 on days 1, 8 and 15, both intravenously. One 28-day course was specified to be repeated twice. The initial dose of KW-2307 was 15 mg/m2 and increased to 20 mg/m2 and then to 25 mg/m2. The numbers of enrolled subjects for each dose were 5, 8 and 12 cases, respectively, in the total 25 cases. This regimen as well as KW-2307 monotherapy induced leukocytopenia (neutropenia) as the main adverse reaction. The coadministration with CDDP tended to increase the occurrence of anorexia and nausea/vomiting. Tumor response was obtained in 5 among 24 evaluable cases (CR1, PR 4). The response rate in the cases untreated with KW-2307 and given at 20 mg/m2 or higher doses was 29.4% (5/17, 95% confidence interval of the response rate: 10.3 to 54.7%). Considering drug compliance, etc., the maximum tolerated dose in this regimen was supposed to be 25 mg/m2, and the recommended dose in phase-II study to be 20 mg/m2.
Adenocarcinoma↗
New anticancer drugs under clinical trials in Japan.
A total of 16 drugs developed in Japan are currently under Phase I or II trials. This article reviews results of some studies of these drugs. Studies included in the article are of SM-5887, MX-2, DWA2114R, and CPT-11.
Animals↗
[Phase I clinical study of 21-consecutive-day oral administration of etoposide].
We conducted a multi-institutional phase I clinical study on a 21-consecutive-day oral administration of etoposide in 12 patients with malignant tumor. The initial dose was 25 mg/body/day and then raised to 50 mg/body/day and eventually to 75 mg/body/day. The dose limiting factor was leukopenia and the maximum tolerated dose (MTD) was 75 mg/body/day. Leukopenia was observed in all 4 patients registered at 75 mg/body/day. Two of 4 patients showed WBC count nadirs of less than 2,000/microliters. The two patients had less than 1.5 m2 body surface area. Thrombocytopenia and hemoglobin decrease were mild compared to leukopenia. Other adverse reactions were as follows; anorexia (75.0%), nausea/vomiting (58.3%) alopecia (46.1%). No sign of accumulation after 21-consecutive-day oral administration of etoposide was seen on pharmacokinetic parameters. As for anti-tumor efficacy, a partial response was noted in a patient with lung metastasis of cervical cancer at the 75 mg/body/day dose level. A recommended dose for phase II study was 75 mg/body/day for 21 consecutive days with a one-week interval. However, for a patient with a body surface area less than 1.5 m2 or with a severe prior chemotherapy, 50 mg/body/day would be considered appropriate.
Administration, Oral↗
Predominantly tumor-limited expression of a mutant allele in a Japanese family carrying a germline p53 mutation.
Germline mutations of p53 have been implicated as a cause of cancer susceptibility in the Li-Fraumeni syndrome. Since inactivation of p53 has been suggested to play an important causative role in lung cancer, the present study of the prevalence of germline mutations in 148 patients with this neoplasm was performed. None of 138 randomly chosen patients were found to carry such mutations, while a single patient had a nonsense mutation at codon 213 among 10 patients selected for early onset and/or occurrence of multiple primary cancers. In contrast to the previous report of biallelic expression of p53 in a case with a germline missense mutation, preferential expression of the wild-type allele was observed in the heterozygous state in both normal lung and peripheral blood lymphocytes of our case, whereas expression of mutant mRNA was readily detectable in her lung cancer in the absence of the remaining wild-type allele. Interestingly, the family history of the proband showed a mild aggregation of adulthood cancers and a high prevalence of stomach cancer, a rare component in American families affected by the syndrome. These observations suggest the presence of heterogeneity with regard to molecular and clinical features of germline p53 mutations.
Adult↗
[An early phase II study of CPT-11 (irinotecan hydrochloride) in patients with hematological malignancies].
An early phase II study of CPT-11 (irinotecan hydrochloride) was conducted in patients with hematological malignancies by 4 administration regimens in a cooperative study involving 13 institutes in Japan. The overall response rate was 23% (7/30) for non-Hodgkin's lymphoma, 33% (1/3) for Hodgkin's disease, 18% (2/11) for acute lymphoblastic leukemia and 7% (1/15) for acute myelogenous leukemia. One PR was also obtained in a patient with chronic myelogenous leukemia. Among responders, 6 relapsed and refractory malignant lymphomas (ML) and 2 relapsed and refractory acute leukemias (AL) were involved. The response rates in ML with the regimens B (40 mg/m2 for 5 days every 3-4 weeks) and C (40 mg/m2 for 3 days every weeks) were 31% (5/16) and 33% (3/9), respectively. The other regimens (regimen A, 200 mg/m2 once a day every 3-4 weeks and regimen D) resulted in no response. Responses in AL were only observed in regimen D (20 mg/m2 twice a day for 7 days every 3-4 weeks). Major toxicities were leukopenia (91%), nausea/vomiting (74%), diarrhea (73%) and anorexia (64%). The incidence of severe gastrointestinal symptoms was higher in regimen B than regimen C. Further studies are warranted to confirm the effectiveness and safety of CPT-11 against ML and AL. The recommended administration schedule was regimen C for ML and regimen D for AL.
Adolescent↗
Development and application of an enzyme immunoassay for tenascin.
A sandwich enzyme immunoassay system for detecting tenascin in human serum was established using purified antibodies to tenascin. The assay system comprises polystyrene balls with immobilized polyclonal antibody F(ab')2 fragments and monoclonal antibody F(ab')2 fragments labeled with beta-D-galactosidase from Escherichia coli. The assay system has a minimum detectable sensitivity of 10 ng/ml of tenascin in human serum, with an assay range of 3 micrograms/ml. The assay system was found not to cross-react with laminin, vitronectin, human epidermal growth factor, fibrinogen, or fibronectin. Coefficients of variation within-run and between-run for the assay of human serum tenascin were less than 10%. Serum samples from healthy adults (n = 86) contained about 800 ng/ml and serum tenascin concentrations of patients with carcinoma (n = 47) were increased. These results suggest that tenascin in serum might be a marker substance for carcinoma.
Adult↗