New drugs for the treatment of lung cancer. The Tokyo Cooperative Oncology Group.
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Antineoplastic Agents↗
Biomedical subjects
K Furuse
Publications and source records attributed to K Furuse.
[Clinical evaluation of 2 mg granisetron tablet for nausea and vomiting induced by anticancer drugs including cisplatin].
1. The clinical efficacy and safety of the 2 mg granisetron tablet were assessed in 32 mainly lung cancer patients who were to receive treatment with anticancer drugs including CDDP. 2. One 2 mg granisetron tablet was administered prophylactically one hour before the start of CDDP administration. 3. Based on the development of nausea and vomiting in 24 hours after the start of CDDP administration, the study medication was judged to be "remarkably effective" or "effective" in 71.0% (22/31) of cases. 4. The study medication was judged to be "safe" in 96.9% (31/32) of cases, without causing any adverse reactions. 5. The above results indicate that the 2 mg granisetron tablet is safe and useful.
Adult↗
[Correlation between the tumor marker Pro-GRP and prognosis in patients with small-cell lung cancer].
We studied 90 patients with small-cell lung cancer in whom levels of Pro-GRP were abnormally high before therapy. Changes in the serum Pro-GRP level have been said to correlate strongly with therapeutic responses in patients with small-cell lung cancer. We found that changes in the serum Pro-GRP level (half-life > or = 30 vs < 30 days) were a significant prognostic factor. Multivariate analysis showed that in these patients the Pro-GRP level after therapy, Performance Status, and age were independent prognostic factors.
Adult↗
[Lung cancer].
Recently, a number of novel chemotherapeutic agents under development show consider able promise in the treatment of lung cancer. Optimally, these new agents should exhibit a unique mechanism of action, a favorable toxicity profile in comparison to standard cisplatin-based chemotherapy, significant single agent activity (> 20% response rate, or > 40% 1-year survival rate) and synergistic antitumor effects with cisplatin and/or radiation. This review will describe the current development status of these new agents, including paclitaxel, docetaxel, vinorelbine, CPT-11, topotecan and gemcitabine.
Antimetabolites, Antineoplastic↗
[The recent progress in chemoradiotherapy of lung cancer].
This is a review of the recent progress in chemoradiotherapy of locally advanced lung cancer. In the limited disease stage of small cell lung cancer, a meta-analysis showed patients treated with a combination of chemotherapy and radiotherapy have a statistically significantly longer survival than those with chemotherapy alone. However, the timing of the combination of radiation and chemotherapy has not been clarified. One study favored late over early use of radiotherapy for survival. Another randomized study and a meta-analysis revealed earlier radiotherapy had a better prognosis. JCOG performed a randomized phase III study comparing concurrent chemoradiotherapy with chemotherapy followed by radiotherapy, and the final results will be published in the near future. In the past, radiotherapy alone had been considered standard therapy for inoperable locally advanced non-small cell lung cancer. Several randomized studies and meta-analyses demonstrated the combination of chemotherapy and radiotherapy produced better survival rates than by radiotherapy alone. Our randomized study indicated the addition of radiotherapy after chemotherapy is superior in long-term survival to chemotherapy alone. The West Japan Lung Cancer Group conduct a phase III randomized study comparing concurrent and sequential chemoradiotherapy, and the determination of survival is now in the follow-up stage. The role of induction chemoradiotherapy before surgical resection, comparison of chemoradiotherapy with induction chemoradiotherapy followed by surgery, and the effects and safety of the combination of new drugs and radiotherapy are now under investigation.
Antineoplastic Agents↗
Dose escalation study of carboplatin with fixed-dose etoposide plus granulocyte-colony stimulating factor in patients with small cell lung carcinoma. A study of the Lung Cancer Study Group of West Japan.
BACKGROUND: We performed a Phase I-II trial to determine the maximum tolerated dose of carboplatin (CBDCA) with a fixed dose of VP-16 and granulocyte-colony stimulating factor (G-CSF) in small cell lung cancer (SCLC) patients. METHODS: Treatment consisted of a starting dose of CBDCA, 400 mg/m2 (i.v., Day 1); VP-16, 100 mg/m2 (i.v., Days 1-3), and G-CSF, 2 micrograms/kg (s.c., Days 4-17) every 4 weeks for four cycles. The dose of CBDCA was escalated in increments of 50 mg/m2 until Grade IV toxicity on the World Health Organization scale developed in two-thirds or more of the patients. RESULTS: Seventy-five previously untreated patients with pathology confirmed SCLC were entered into the trial. Seventy-one patients were eligible and 70 patients were evaluated for response. Forty-five patients had limited disease (LD) and 26 had extensive disease (ED). The response rate of the 70 patients who could be evaluated was 81%, with 23% attaining a complete response (CR) and 58% attaining a partial response (PR). The response rate was 80% in LD patients (CR, 23%; PR, 57%) and 85% in ED patients (CR, 23%; PR, 62%). The major dose-limiting toxicity was thrombocytopenia. Nephrotoxicity, neurotoxicity, and ototoxicity were uncommon. The doses of CBDCA that resulted in unacceptable thrombocytopenia were 700 mg/m2 in patients younger than 70 years and 500 mg/m2 in patients older than 70 years. Overall median survival time (MST) was 9 months. MST of LD patients and ED patients were 11 months and 7 months, respectively. The dose-limiting toxicity of CBDCA with a fixed dose of VP-16 and using G-CSF as bone marrow rescue was age-related thrombocytopenia. The maximum tolerated dose of CBDCA was 650 mg/m2 if patients were younger than 70 years and 450 mg/m2 if they were 70 years or older. CONCLUSIONS: When we retrospectively compared our results with those using standard chemotherapy regimens, we saw no therapeutic benefit from increasing planned doses of CBDCA up to 700 mg/m2 in combination with G-CSF in patients with SCLC.
Aged↗
Clinicopathological significance of Ki-ras point mutation and p21 expression in benign and malignant exocrine tumors of the human pancreas.
CONCLUSION: The present study suggests that Ki-ras point mutations may play an important role in the early stages of tumorigenesis and that a double mutation has a stronger detrimental effect than a single mutation on the survival after pancreatectomy. BACKGROUND: Previous studies have suggested the important role of Ki-ras point mutations in ras gene codon 12 in the tumorigenesis of pancreatic cancer, but their clinicopathological significance is still unclear. The present study was designed to assess the clinicopathological significance of Ki-ras point mutations, and p21 expression in malignant and benign diseases of the pancreas. METHODS: Oligonucleotide dot-blot hybridization for Ki-ras point mutations in codon 12 and immunohistochemical staining for p21 expression were applied. Cases included 44 primary and 15 metastatic lesions of pancreatic cancer, and 17 benign pancreatic diseases. RESULTS: Ki-ras point mutations and p21 expression were detected in 43 and 19 primary lesions, 9 and 6 metastatic lesions, and four and five benign diseases, respectively. The patients with a single mutation had a better survival after pancreatectomy than those with a double mutation. The patients with a p21(+) GAT mutation showed the worst survival after pancreatectomy compared with other categories of patients.
Adult↗
Phase II study of recombinant human interleukin 3 administration following carboplatin and etoposide chemotherapy in small-cell lung cancer patients. SDZ ILE 964 (IL-3) Study.
Recombinant human interleukin 3 (rhIL-3) has been suggested to be a useful agent for the treatment of chemotherapy-induced thrombocytopenia. For evaluation of this possibility, rhIL-3 was given subcutaneously for 10 days to patients with small-cell lung cancer (SCLC). Chemotherapy consisted of carboplatin (CBDCA) given at 400 mg/m2 to previously untreated patients or at 350 mg/m2 to previously treated patients on day 1 and etoposide (VP-16) given at 100 mg/m2 on days 1-3 every 4 weeks. If the platelet count nadir was < 75,000/microliters in the control cycle of chemotherapy, patients were randomly assigned for the next cycle to rhIL-3 given at 5 or 10 micrograms/kg per day on days 4-13. A total of 41 patients (32 previously untreated patients and 9 previously treated patients) were enrolled in the study. The platelet count nadir in the cycles including rhIL-3 was significantly higher at both dose levels (P < 0.01) than in the control cycle. The duration of thrombocytopenia (< 75,000/microliters) and the mean time from the 1st day of chemotherapy to thrombocyte recovery (> 100,000/microliters) in the rhIL-3 cycle were significantly shorter than those in the control cycle (P < 0.01). The neutrophil count nadir and the duration of neutropenia (<1,000/microliters) were also significantly improved in the rhIL-3 cycle (P < 0.05). The major side effects were fever (80.5%), headache (24.3%), and fatigue (14.6%). All side effects were tolerable and of less than grade II. There was no difference in the efficacy of the two dose levels, but the 5-micrograms/kg dose appeared to be better tolerated than the 10-micrograms/ kg dose. We conclude that rhIL-3 administration following chemotherapy consisting of CBDCA and VP-16 reduces the incidence and severity of chemotherapy-induced thrombocytopenia and neutropenia with an acceptable adverse-events profile.
Adult↗
Management of malignant tracheobronchial stenosis with metal stents and Dumon stents.
BACKGROUND: Tracheobronchial stenosis caused by malignancy is a life- threatening problem. Stenting is one of the treatment modalities and recently has been used widely for the management of such stenosis, but we do not have a clear guide as to which stent should be selected. METHODS: We evaluated 25 patients (19 men, 6 women; mean age, 60.7 years; range, 34 to 77 years) received 24 metal stents (four covered with silicone rubber) and three Dumon stents. All 25 patients had severe dyspnea because of airway stenosis caused by malignant tumors. RESULTS: Among the 25 patients, airway obstruction due to extrinsic compression by tumor developed in 11 and was treated with a bare metal stent. The airway remained patent in 10 patients. In 16 patients with intraluminal tumor invasion, nine lesions were treated with a bare metal stent, four lesions with a covered metal stent, and the remaining three lesions with a Dumon stent. Recurrent stenosis did not occur in any patient with a covered metal stent or a Dumon stent. However, restenosis occurred in 4 patients with a bare metal stent, all of whom received laser therapy. In all patients, stenting immediately relieved dyspnea. Six patients lived for 32 days to 53 months after stenting, and 19 patients died of primary malignancies with a mean survival of 131.9 days. CONCLUSIONS: Metal stents are effective in treating malignant extrinsic tracheobronchial compression. The use of covered metal stents or Dumon stents is preferable for intraluminal stenosis due to malignant growth.
Adult↗
Randomized study of vinorelbine (VRB) versus vindesine (VDS) in previously untreated stage IIIB or IV non-small-cell lung cancer (NSCLC). The Japan Vinorelbine Lung Cancer Cooperative Study Group.
PURPOSE: We compared the activity of vinorelbine (VRB) and vindesine (VDS) in a randomized crossover study in patients with previously untreated stages IIIB or IV non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Two hundred four patients were assessable for response and toxicity. VRB was administered at a dose of 25 mg/m2 weekly and VDS at a dose of 3 mg/m2 weekly. Patients who failed to respond after 4 cycles of initial monotherapy were switched to a combination chemotherapy (VRB-->VDS + cisplatin (P) or VDS-->VRB + P). RESULTS: Objective response was observed in 31.1% of patients in the VRB arm versus 8.9% of those in the VDS arm (P = 0.0002). The median duration of response to VRB was 18.5+ weeks (range, 7.9 to 107.5+ weeks) compared with 11.7+ weeks (range, 6.0 to 35.0+ weeks) for VDS. Of the 69 patients who failed to respond to initial monotherapy, 33 in the VRB group who subsequently received VDS + P did not respond and 13 (26.5%) of 49 initially on VDS who received subsequent VRB + P responded. The rates of grades 3 and 4 leukopenia were similar in the two monotherapy arms (VRB, 55.3% vs. VDS, 48.5%). However, grade 3 anemia was more frequent in the patients on VRB than in those on VDS. The incidence of peripheral neurotoxicity was significantly higher with VDS than with VRB (P = 0.002), but VRB induced a slightly higher rate of local cutaneous reaction than VDS (P = 0.012). With the combination of cisplatin and these vinca alkaloids, peripheral neurotoxicity was less frequent in the VRB group than in the VDS group. CONCLUSION: Our results demonstrate that VRB yields a higher response rate than VDS in stage IIIB or IV NSCLC, with the same extent of toxicity in terms of leukocytopenia. The peripheral neurotoxic effects were also milder with VRB than with VDS. In second-line chemotherapy, there was a notable difference in response between the VRB + P and VDS + P regimens.
Adult↗
Dose-escalation study of oral etoposide and carboplatin in patients with advanced lung cancer.
A dose-escalation study of daily etoposide and carboplatin was carried out on 23 patients with advanced lung cancer using a starting dose of 40 mg/m2/day etoposide given orally for 21 days and 250 mg/m2 carboplatin given intravenously (IV) on day 1. A total of 41 courses were given. Myelosuppression was the major dose-limiting toxicity. The maximum tolerated dose was reached at the fourth level with 40 mg/m2/day etoposide for 21 days and 400 mg/m2 carboplatin on day 1, once every 4 weeks. Non-hematological toxicities were generally mild or reversible. The recommended doses of this combination chemotherapy are 40 mg/m2/day etoposide for 21 days and 350 mg/m2 carboplatin on day 1. The response rate for non-small cell lung cancer and small cell lung cancer was 16.7% and 60% (95% confidence intervals of 3.6% to 41.4%, and 14.7% to 94.7%), respectively. A phase II study is necessary to define the efficacy and safety of this combination chemotherapy.
Administration, Oral↗
A case of malignant pleural mesothelioma with metastasis to the orbit.
A 58-year-old woman with malignant mesothelioma metastatic to the orbit is reported. Malignant pleural mesothelioma was diagnosed by pleural biopsy. Marked reduction of pleural effusion was obtained with intrapleural interleukin-2 therapy. Systemic chemotherapy failed to elicit a response after the first recurrence of the tumor. Multiple systemic metastasis, including metastasis to the orbit, developed and the patient died one year and 4 months after the initial diagnosis. Although malignant mesothelioma is known to spread hematogenously, sometimes producing brain metastasis, there have been few reports of orbital metastasis, and in fact the present report may be the first clinically documented account of its kind.
Female↗
Determinants of myelosuppression in the treatment of non-small cell lung cancer with cisplatin-containing chemotherapy.
Data on 16 potential risk factors for myelosuppression were assessed in 134 patients who received either vindesine and cisplatin (VP) or mitomycin C, vindesine and cisplatin (MVP) for inoperable stage III or IV non-small cell lung cancer in a randomized trial. Determinant factors for myelosuppression were evaluated by using univariate analysis and the logistic regression model. Recursive partitioning and amalgamation (RPA) was also used to define patient subgroups frequently suffering from severe bone marrow toxicity. Overall, 33 (25%) of 134 patients experienced at least one episode of grade 4 leukopenia. In univariate analysis, age, body surface area, serum creatinine, and pretreatment hemoglobin concentration were associated with severe leukopenia. A multivariate analysis using the logistic regression method showed that only raised creatinine level was an independent predictor for grade 4 leukopenia (P = 0.049). The RPA model generated three distinct subgroups based on age, body surface area and regimen. The three subgroups were distinguished by the frequency of severe (grade 4) leukopenia (50%, 25%, and 2.4%, respectively) (P < 0.001). Grade 4 leukopenia occurred more frequently in patients in class 3 (age > or = 65 years and treatment with MVP). The RPA model was useful in identifying the risk factors for myelosuppression induced by cisplatin-based chemotherapy, and in defining patient subgroups with elevated risk of toxicity.
Adult↗
Phase II trial of docetaxel in previously untreated advanced non-small-cell lung cancer: a Japanese cooperative study.
PURPOSE: This phase II study was conducted to evaluate the efficacy and toxicity of moderate-dose (60 mg/m2) docetaxel in Japanese patients with previously untreated advanced (stage IIIB or IV) non-small-cell lung cancer (NSCLC). PATIENTS AND METHODS: Docetaxel 60 mg/m2 was administered intravenously over 1 to 2 hours to patients with previously untreated stage IIIB or IV NSCLC. Treatment was repeated every 3 weeks. No routine premedication was given. The patients' median age was 67 years (range, 40 to 80). Forty-four patients (59%) had adenocarcinoma and 55 (73%) had stage IV disease. The median Eastern Cooperative Oncology Group (ECOG) performance status (PS) was 1. RESULTS: Seventy-five patients were eligible and treated with docetaxel. Fourteen patients (19%) achieved a partial response (PR); response was not significantly affected by histology or clinical stage. The median survival time for all patients was 297 days. The predominant toxicity was neutropenia, with 87% of patients experiencing grade 3 or 4. Febrile neutropenia was seen in eight patients. Hypersensitivity and edema each occurred in only 4% of patients and were easily manageable. There was no possible treatment-related death of acute exacerbation of pneumonitis. CONCLUSION: Docetaxel 60 mg/m2 showed significant activity in advanced NSCLC, with a low incidence of hypersensitivity or peripheral edema. Further investigation of this agent in NSCLC is warranted, especially in combination with other active drugs.
Adenocarcinoma↗
[Photodynamic therapy of centrally located early-stage lung cancer].
Photodynamic therapy (PDT) with photofrin II and excimer dye laser has an excellent effect on patients (pts) with centrally located early-stage lung cancer with a limited tumor length of 1 cm or less and a clearly visible tumor margin. Further, to expand the therapeutic area of PDT to these early-stage lung cancers, it is necessary to exploit more powerful laser equipment and more sensitive sensitizers. Also, it is essential in the decision to treat early-stage lung cancer to evaluate whether PDT can be used as an effective alternative therapy to surgery in patients with operable centrally located early-stage lung cancer. Finally, it is an important issue for the treatment of centrally located early-stage lung cancer to determine which therapeutic modalities have to be selected as the initial choice in endoscopic therapy.
Antineoplastic Agents↗
[Early phase II study of BMS-181339 (paclitaxel) in patients with non-small cell lung cancer. BMS-181339 Non-Small Cell Lung Cancer Study Group].
We conducted a multi-institutional (11 facilities), early phase II study of BMS-181339 (paclitaxel), a novel anti-cancer drug, for non-small cell lung cancer (NSCLC). The 150 mg/m2 dose of paclitaxel was given by intravenous infusion over 24 hours every three weeks. When fifteen patients were accumulated, the interim review revealed that three of 15 eligible patients had a partial response for a response rate of 20%. The most common toxic effects were grade 3 or 4 leukopenia seen in 73.3% (11/15), and grade 4 neutropenia in 93.3% (14/15). One patient with neutropenia had suspected septic shock, which could be managed by G-CSF and antibiotics. No serious hypersensitivity reaction was seen with premedication of anti-allergic drugs, although mild allergic reactions such as skin rash and flush, were observed in 20.0% (3/15). Other adverse reactions, including alopecia, fever, arthralgia, myalgia and peripheral neuropathy, were mild in most cases. We conclude that it is relevant to proceed to a late phase II study for NSCLC.
Adult↗
[LY188011 phase I study. Research Group of Gemcitabine (LY188011)].
LY188011 (Gemcitabine hydrochloride) is a new derivative of deoxycytidine. Phase I study was carried out by a cooperative study group. LY188011 was administered weekly for 3 consecutive weeks starting with an initial dose of 60 mg/m2 (1n) and then increasing the dosage to 1,000 mg/m2 (16.7n). Dose limiting factor was found to be myelosuppression (decreases of WBC, neutrophils and platelet), and MTD was considered to be 1,000 mg/m2. The nadir of WBC and platelet were observed after about 1-3 weeks. It took 1-2 weeks for their recovery. Other adverse reactions included fever, fatigue, anorexia, nausea/vomiting, anemia and transient elevations of GOT and GPT. However, those adverse reactions were mild. T1/2 rho of plasma concentration was about 19 min and the C5min was dependent on the dose. Anti-cancer effects were observed in one gastric cancer and two colon cancer patients. It is recommended that the dosing schedule for an early phase II study is 800 mg/m2 weekly for 3 weeks with 1 week of rest as one cycle, in multiple cycles.
Adult↗
[Phase I study on DMDC].
Phase I study on antimetabolic carcinostatic DMDC was conducted at 16 medical institutions nationwide for patients with various types of malignant tumors. DMDC was administered by intravenous infusion as per the following three schedules: single administration, single repeated administration, and 5-consecutive-day administration. The safety of the compound was examined single administration in 16 patients, by the single repeated administration in 5 patients, and by the 5 consecutive-day administration in 7 patients, for a total of 28 patients. In the single administration trial, 200 mg/m2 (1 n) was given as an initial dose, then increased stepwise to 450 mg/m2 (2.25 n). The single repeated administration trial was conducted at a single dose of 300 mg/m2. One treatment course lasts until recovery from side effects and abnormalities in laboratory test values. As a general rule, the administration was repeated for 2 treatment courses or more. In the 5-consecutive-day administration trial, an initial dose was 30 mg/m2/day (1 n), and increased to 40 mg/m2/day (1.3 n). The dose-limiting factors for both the single and 5-consecutive-day administration trials were decreases in the numbers of leukocytes and neutrophils. The maximum tolerated dose for single administration trial was over 400 mg/m2 (2 n), and for the 5-consecutive-day administration trial 40 mg/m2 (1.3 n). The decrease in the number of leukocytes and neutrophils for both the single administration and 5-consecutive-day administration trial reached its nadir one to two weeks after administration, and recovered in about one week. In the single repeated administration trial, the administration interval for patients who had completed 2 courses was 2 approximately 3 weeks. The plasma half-life of DMDC in the final phase of elimination in the single administration trial was 5.2 approximately 6.3 hours, and no differences were seen among dose levels. The urinary excretion rate was between 32.0 approximately 61.5% until 48 hours after administration. No accumulation was seen in the 5-consecutive-day administration trial. There were no findings to suggest an antitumor effect in the present study. Given the recovery pattern for suppression of marrow, the above mentioned results led us to decide that an recommended method of administration and dosage in an early phase II trial would be 300 mg/m2 per administration by an intravenous infusion every 2 approximately 3 weeks.
Aged↗