Search

A 53-year-old female was admitted to our hospital complaining of disturbance of consciousness and hallucinations. About one year and 5 months ago she had adenocarcinoma of the lung, which was treated with surgery and chemotherapy. Computed tomography and magnetic resonance imaging revealed that her lung cancer had relapsed as caricinomatous meningitis and multiple lung metastases. She was treated with erlotinib, which rapidly resulted in disappearance of her symptoms. She still continues to receive erlotinib therapy without suffering from evident relapse 7 months after the initiation of the treatment.

Some large-scale clinical investigations on gefitinib-induced lung injury have been performed,which have much new information about anticancer drug-induced lung injuries and indicated significant problems in the development of new anticancer drugs. Analysis of gefitinib-induced lung injury revealed varying patterns of clinical features, ethnic differences in onset, risk factors for development and diagnostic difficulties in anticancer drug-induced lung injuries. Furthermore, we realized again underlying problems in the process of developing new anticancer drugs and the importance of post-marketing surveillance. We must elucidate the mechanism of anticancer drug-induced lung injuries to manage them effectively.

The current status and measures for anticancer drug-induced lung injury and radiation pneumonia in cancer treatment were reviewed. Interstitial pneumonia induced by anticancer drugs is pathologically classified into the following: chronic interstitial pneumonia (CIP) or nonspecific interstitial pneumonia (NSIP), eosinophlic pneumonia (EP), bronchiolitis obliterans-organizing pneumonia (BOOP), diffuse alveolar damage (DAD), and hypersensitivity pneumonia (HP). In these pulmonary reactions to anticancer drugs, interstitial pneumonia manifested by DAD, which shows the acute or chronic clinical course, presents high mortality rates. Therefore, special care should be taken when DAD develops. Radiation pneumonia has two clinical phases, an acute phase of injury termed radiation pneumonitis, and a chronic phase of injuring termed lung fibrosis. It is usually confined to the irradiated area. On the other hand, sporadic radiation pneumonitis occurring outside the irradiated area has been reported besides classic radiation pneumonitis. Pathologically, it shows lymphocytic alveolitis or BOOP. Although radiation pneumonia has a good prognosis, mortality is rarely observed when lesion spreads outside the irradiated area.

The multinational, multi-institutional clinical Phase II trial of gefitinib monotherapy, IDEAL (IRESSA Dose Evaluation in Advanced Lung Cancer) 1, included Japanese and non-Japanese patients with advanced non-small-cell lung cancer (NSCLC) pretreated with one or more chemotherapy regimens, at least one including platinum. To investigate whether survival is affected by gender or histological type of cancer, a retrospective, exploratory subset analysis was conducted including only Japanese patients from IDEAL 1 (n = 102 in total, 51 each in 250 and 500 mg/day groups). The median survival time of the 102 patients was 12.0 months and the one year survival rate was 50%. The median survival time was 13.8 months for the 250 mg/day group and 11.2 months for the 500 mg/day group and the one-year survival rate was 57% and 45% respectively. Survival was longer in patients with adenocarcinoma than those with other histological types of cancer, and was longer in those with symptom improvement than without. The median survival time in females was longer than that in males. The results suggest that gefitinib could be superior to classical anticancer agents with regard to not only the response rate but also survival time in patients with NSCLC, particularly adenocarcinoma, previously treated with chemotherapy. Further studies are needed to identify factors affecting survival.

Gefitinib is an epidermal growth factor receptor (EGFR) inhibitor that is reported to be well tolerated and active in patients with chemotherapy-resistant non small cell lung cancer. On the other hand, gefitinib was also reported to produce a severe adverse event, interstitial lung disease, in less than 2% of treated patients. Given these circumstances, it is important to evaluate this drug and to establish its use clinically. We do not have sufficient data to evaluate gefitinib at this time. Phase III study of second/third line or maintenance therapy using gefitinib is required for such an evaluation. The development of individualized therapy with gefitinib might be also be required.

It is widely known that patients with idiopathic pulmonary fibrosis (IPF) are frequently associated with lung cancer. Although a complication with lung cancer is an important prognostic factor for IPF, standard treatments for lung cancer cannot be given because of IPF. Especially, the administration of many anticancer agents is limited by a complication with IPF, which is recognized as a risk factor for the development of fatal lung injury in cancer chemotherapy. Epidemiological studies reveal that cigarette smoking and occupational and environmental exposure to toxic substances are common risk factors for both IPF and lung cancer. It has been assumed that metaplasia in fibrous lesions is pathologically a precancerous lesion, but it is necessary to prove several genetic abnormalities in the process of carcinogenesis in order to clarify that. Currently, several genetic abnormalities in IPF, including in p53, K-ras, FHIT and transforming growth factor (TGF)-beta 1 type II receptor, have been reported.

Irinotecan and its active metabolite, SN-38, were reported to have the absorption characteristics of weakly basic drugs. Moreover, stasis of these compounds is thought to induce damage to the intestinal mucous membrane. The purpose of this report was to examine whether oral alkalization (OA) combined with control of defecation (CD) might prevent irinotecan-induced side effects. From day one of irinotecan infusion to day four, OA & CD were practiced using orally administered sodium bicarbonate, magnesium oxide, basic water, and ursodeoxycholic acid. Thirty-two lung cancer patients were treated with irinotecan in combination with cisplatin in the absence of OA & CD (Group A). Thirty-seven patients matched for background characteristics were treated with the same regimen in the presence of OA & CD (Group B). Group B had a reduced incidence of delayed diarrhea (Grade 2 < or = Group A 32.3% vs. Group B 9.4%), nausea, vomiting, and myelotoxicity, especially granulocytopenia compared with Group A. In addition, dose intensification was well-tolerated in Group B. Tumor response rates for non-small cell lung cancer were 59.3% (16/27 patients) in Group B against 38.5% (10/26 patients) in Group A. OA & CD appears to reduce the irinotecan-induced side effects, especially delayed diarrhea. Risk factors statistically associated with delayed diarrhea include advanced age and the use of irinotecan without OA & CD.

Transforming Growth Factor-beta 1 (TGF-beta 1) regulates the proliferation of normal epithelial cells, and resistance to TGF-beta 1 growth inhibition is a common feature of human cancers including lung cancer. In order to understand the mechanism of resistance to growth inhibition by TGF-beta 1 and to reverse the regulation of proliferation in lung cancer, we determined the genomic structure of the genes involved in the signal transduction pathway of TGF-beta 1 and performed an initial mutation survey of the complete coding region of the genes in lung cancer and cell lines with the resistance to growth inhibition by TGF-beta 1. First, a mutation analysis of the TGF-beta type II receptor (TGF-beta RII) was performed. Point mutations of the gene were detected in several colon cancers and an adenocarcinoma of the lung in the poly-A sequence. No mutations of Smad 2, 3, 4, 5 and TGF-beta type I receptor (TGF-beta IR) genes were detected in a series of the tumors we tested, although several mutations of Smad 2 and 4 were previously reported. Frequent alterations of the p15 gene and reduced expression of p21 we already reported from our previous studies. We also determined the genomic structure of the mannose 6-phosphate/insulin-like growth factor 2 receptor (M6P/IGF2R), which is involved in activating TGF-beta 1, and performed an initial mutation survey of the complete coding sequences of the gene. A point mutation at exon 40 was found in one lung adenocarcinoma cell line. In summary, alterations in the many genes involved in the signal transduction of TGF-beta 1 were found and may mediate the loss of TGF-beta 1 responsiveness in lung cancer. The molecular targets for the regulation of the proliferation of lung cancer are thought to be p15, p21 and the transcriptional regulators.

It was reported from a previous randomized trial (NEJM 329: 1848, 1993) that a moderate increase in the initial dose of cyclophosphamide and cisplatin improves the survival of patients with LDSCLC. Rapid administration of several active agents over a short treatment period, such as the CODE regimen, is a potentially usefully strategy for increasing the initial dose intensity. Based on these findings, we conducted a pilot study of CODE (C: 25 mg/m2, day 1, weeks 1-4, O: 1 mg/m2, day 1, weeks 2, 4, D: 40 mg/m2, day 1, weeks 1, 3, E: 80 mg/m2, days 1-3, weeks 1, 3) chemotherapy for the first 4 weeks followed by PE therapy (P: 80 mg/m2, day 1, E: 100 mg/m2, days 1-3, for 3 cycles) with concurrent TRT (1.5 Gy bid x 30 fr., total 45 Gy) to treat LDSCLC. From June 1996 through September 1996, 23 patients (pts) were enrolled, among whom 22 were eligible. The patients' characteristics were as follows: median age 65; M/F, 15/7; PS, 0/1/2,9/9/4; Stage II/IIIA/IIIB, 3/8/11. The relative dose intensities in the CODE phase for patients who received this treatment were 107% for P and 156% for E, compared with standard PE therapy. No treatment related death occurred in this series. Myelosuppression was the most frequent toxicity in both treatments. Grade 3 and 4 leukopenia and neutropenia occurred in 73% and 86% of patients in the CODE phase, and in 83% and 91% in the PE phase, respectively. Thrombocytopenia occurred in 14% of the patients in the CODE phase and in 37% in the cisplatin-etoposide phase. Other non-hematological toxicities were mild. There was no severe esophagitis or pneumonitis following radiation therapy. CR was observed in 13 (59%) of the 22 patients, and 9 (41%) patients showed PR, giving an overall response rate of 100%. A median survival time has not yet been ascertained. Our preliminary results indicate that CODE therapy followed by PE therapy with concurrent TRT has very high activity with acceptable toxicities. This treatment regimen should be compared with PE therapy and concurrent TRT in a randomized trial.

A multicenter cooperative phase I study of ZD-1694 (raltitrexed), a novel, folate-based thymidylate synthase (TS) inhibitor, was conducted with single and repeated doses in 30 patients with various malignant tumors. ZD-1694 was intravenously infused over 15 minutes. In the single-dose study, the initial dose was fixed at 1.0 mg/m2 (1n), and the dose was escalated stepwise up to 3.5 mg/m2 (3.5 n). Based on the results of the single-dose study, in the repeated-dose study, doses of 2.5 n and 3 n were infused every three weeks (3 weeks/one course). In principle, patients received 2 courses or more. Of the 29 eligible patients, 16 were in the single-dose study and 13 in the repeated-dose study. Adverse reactions were evaluated in all eligible patients. In the single-dose study, neutropenia, nausea/vomiting, diarrhea, and transaminase (GOT, GPT) increases, of grade 3 or higher, occurred at high doses of 3 n and 3.5 n. These were regarded as dose-limiting toxicities (DLT). DLT of grade 3 or higher were observed in 1 of 4 patients given 3 n and 2 of 4 patients given 3.5 n. These results suggested that the maximum tolerated dose (MTD) of ZD-1694 was 3.5 n (3.5 mg/m2). In the repeated-dose study, DLT of grade 3 or higher was observed in no more than one third of each dose group, 2 of the 6 patients given 2.5 n and 2 of the 7 patients given 3 n. These results suggested that 3 n (3.0 mg/m2), a dose nearer to MTD, was the recommended dose for the phase II study. Although transaminase increases were observed in all patients, in 12 of them the increase was grade 2 or lower and reversible. A pharmacokinetic investigation showed the mean elimination half life of ZD-1694 plasma concentration was 91.5 hours in the single-dose group and 119.1 hours in the repeated dose group. It was suggested that ZD-1694 is metabolized to polyglutamates after uptake and retained in the cells for a long duration. However, no accumulation was seen in plasma concentration of ZD-1694 following repeated doses at 3-weekly intervals. One PR was observed in a patient with colorectal cancer receiving 2.5 n in the repeated-dose study. Based on these results, the recommended dosage and administration for the phase II study of ZD-1694 was 3 n (3.0 mg/m2) intravenously infused over 15 minutes every 3 weeks.

Clinical trials of IL-3, IL-11 and thrombopoietin (TPO) against chemotherapy-induced thrombocytopenia were reviewed. Many clinical trials of IL-3 were conducted, which increased the platelet nadir counts and improved the recovery from thrombocytopenia at a dose of 5 micrograms/kg/day for 7 to 14 days. Major side effects, fever and headache, were tolerable. The combination with G-CSF was also examined. IL-11 improved the platelet nadir counts and the recovery from thrombocytopenia at a dose of 50 micrograms/kg/day for 14 days. Adverse events of IL-11 were general fatigue and edema, which were mild. Phase I/II studies of TPO were conducted, which showed a marked increase of platelet counts and improvement in recovery from thrombocytopenia. A few patients experienced mild thrombo-embolism. Improved QOL and survival benefits in the evaluation of these cytokines must be demonstrated.

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.

A 44-year-old premenopausal woman with bone metastases of breast cancer was initially treated with systemic chemotherapy (CEF) and radiation therapy after standard mastectomy. However, progressive change of bone metastases with elevation of tumor markers (CEA, NCC-ST 439) was detected, so continuous administration of LH-RH agonist and combination chemotherapy (CEF) were conducted. Subsequently, complete objective regression was attained after 40 weeks.

AIDS has become a problem for not only researchers and medical staff but also for humankind, since its discovery 10 years ago. To prevent and control AIDS, one must understand the pathology of HIV infection, which is the cause of AIDS, in addition to mass education on correct measures for prophylaxis. In this review, we present the present status of HIV infection in Japan, especially in relation to pulmonary disease and tumor, and we introduce the basic research being carried out for the development of HIV vaccine.

We conducted an early phase II trial in advanced non-small cell lung cancer (NSCLC) to evaluate response efficacy of a combination of Cisplatin (CDDP) and Carboplatin (CBDCA). The twenty-six patients in the study had had no previous treatment. They received a sequential administration of 300 mg/m2 CBDCA and 80 mg/m2 CDDP with approximately 3,500 ml of hydration on day 1 every 4 weeks. All patients were evaluable for response and toxicity. Ten (38.5%) of all assessable patients achieved a partial response (95% confidence interval, 19.8-57.2%). Response rates for patients with stage III A, III B and IV- disease were 40.0 (2/5), 70.0 (7/10) and 9.1% (1/11), respectively. Response rates for patients with squamous cell carcinoma, adenocarcinoma and large cell carcinoma were 35.7 (5/14), 45.5 (5/11) and 0.0% (0/1), respectively. The median survival time (MST) of all patients was 11 months. The MST for patients with stage III disease was 14 months; for those with stage IV disease it was 7 months. The MST for responding patients was 15 months and for not responding patients 5 months. Major toxicities were hematologic and gastrointestinal, and the dose-limiting factor was thrombocytopenia. This combination chemotherapy was effective against NSCLC with tolerable toxicities. Further trials are warranted to determine the efficacy of the combination chemotherapy.

A phase I clinical study of intravenous Tegafur was conducted in nineteen previously treated patients with primary lung cancer. The dose of Tegafur was elevated from 1.0 to 3.0 g/m2/day for five consecutive days to determine the maximum tolerated dose. The dose-limiting factors were gastrointestinal and neurological toxicity and fatigability observed with the dose level of 2.5 g/m2/day for 5 days. Hematologic, hepatic and renal toxicities were not observed. Gastrointestinal toxicity including nausea, vomiting, anorexia and diarrhea of over grade 2 were seen to result from the dose of 2.5 g/m2/day. Neurological toxicity consisted of headache, dizziness, anxiety and depression. At the dose level of 2.0 g/m2/day, one patient, who had epileptic seizures in the past, experienced a psychomotor seizure. Depression (Grade 2 CNS toxicity) was observed at the dose level of 3.0 g/m2/day. Dose limiting factors were neurological toxicities. The pharmacokinetics of tegafur and 5-FU (the active form of Tegafur) has been studied in all patients. Serum level of tegafur was measured by HPLC method, and serum level of 5-FU was analyzed by GC-MS method. At the dose level greater than 2.0 g/m2/day for 5 days, the mean serum 5-FU values appear over the therapeutic range (0.1 micrograms/ml). In conclusion, 2.5 g/m2/day for 5 days was considered to be MTD, and 2.0 g/m2/day for 5 days intravenous administration was recommended for the phase II trial of single agent chemotherapy.

SRCA was performed using surgically removed fresh tissues in 26 cases of lung cancer. The histological examination of day 6 xenograft showed that only a few xenografts contained tumor cells because of the host cell infiltration and stroma. For the assay considered as evaluable, we defined that control mice needed to show delta tumor size larger than -0.5 OMU and histological presence of tumor cell more than 50% in the day 6 xenograft. The evaluable assay rate (EAR) was no more than 25% (4/16). By the pretreatment with X-ray irradiation of 3 Gy, host cell infiltration was significantly suppressed. With this procedure however, only 40% (4/10) of EAR was gained. The reason for this low EAR was due to the difficulty to obtain the specimens enriched with tumor cells because of stroma and necrotic tissue. Then we used specimen obtained from the human lung cancer line xenografted in nude mice, which resulted in a high EAR of 84% (16/19). We concluded that SRCA for fresh surgical materials was still difficult. However SRCA for lung cancer line was feasible, especially for in vivo preclinical chemosensitivity test for new agents and decision for new drug combination. SRCA as a disease oriented chemosensitivity test is expected to develop in the future.

The response and pharmacokinetics of cisplatin instilled into the pleural cavity were studied in 11 patients with malignant pleural effusion; 10 patients had primary lung cancer and one had breast cancer. All of them were adenocarcinoma histologically. In five of the 11 patients effusion disappeared and its cytology became negative for malignancy after four weeks. In the other six patients effusion was reduced and its cytology became negative for malignancy after four weeks. Toxicity was almost similar to that in systemic administration of cisplatin but a few patients had chest pain and fever possibly due to local irritation. The pharmacokinetics showed that a high concentration of cisplatin (free-form, 48.9 micrograms/ml) was maintained over a long period (free from (t 1/2) beta = 33.6 hours) in the pleural cavity. This was regarded as the reason for the high response to this therapy. The intrapleural instillation of cisplatin into the pleural cavity therefore seems to be an effective modality for malignant pleural effusion.