Cis-dichlorodiammine platinum (II) CDDP in the treatment of non-small cell lung cancer

The effect of CDDP was evaluated in 44 cases of non-small cell lung cancer (squamous cell ca. 11 cases, adeno-large cell ca. 33 cases). Administered dosage of CDDP was in the range of 60-100 mg/m2 (60 mg/m2, 80 mg/m2, 100 mg/m2 per individual). 23 cases were treated with CDDP chemotherapy alone while the other 21 cases were combined with Vindesine (VDS). Three cases out of 18 receiving the CDDP monochemotherapy achieved partial response and the response rate was 16.7%. Six cases out of 15 receiving the CDDP + VDS cases achieved partial response and the response rate was 40.0%. Because of slow shrinkage of the lesion as revealed by chest X-ray film, evaluation of CDDP efficacy could only be done after two administrations at 3-4 week intervals. Values of serum creatine and BUN were transiently elevated with a dose-dependent tendency in the monochemotherapy cases. In combination chemotherapy cases bone marrow toxicity was the main dose-limiting factor. This regimen was tolerable and it was concluded that CDDP is a useful agent for combination chemotherapy of non-small cell lung cancer.     

A randomized study of cisplatin versus cisplatin plus vindesine for non-small cell lung carcinoma.

Between August 1983 and March 1985, a randomized study was conducted that compared cisplatin (CDDP) (80 mg/m2 on day 1) alone with CDDP plus vindesine (VDS) (3 mg/m2 on days 1, 8, and 15) in 160 consecutive patients with inoperable non-small cell lung cancer (NSCLC). There were no complete responses. The response rate for CDDP plus VDS (22 of 77 patients, 29%) was significantly higher than that for CDDP alone (9 of 78 patients, 12%) (P less than 0.05). However, no difference existed in the median duration of response (20 weeks for CDDP plus VDS versus 20 weeks for CDDP alone) or the median survival time (45 weeks for CDDP plus VDS versus 39 weeks for CDDP alone). No significant differences in toxicity were detected between the two arms; myelosuppression, alopecia, and peripheral neuropathy occurred more frequently with CDDP plus VDS and there was one lethal episode of hepatorenal syndrome in the CDDP plus VDS arm. Among the variables Eastern Cooperative Oncology Group (ECOG) performance status (PS), age, sex, stage, weight loss, serum lactate dehydrogenase (LDH) level, albumin level, histologic cell type, and chemotherapy arm, only chemotherapy arm was a significant factor leading to a major response (P = 0.019, multiple logistic regression analysis). The significant predictors of survival were PS (P = 0.000), sex (P = 0.000), and stage (P = 0.002) (Cox's proportional hazards model), with a PS of 0 or 1, female sex, and lower stage yielding the best survival. Although a significantly higher response rate was obtained in the combination arm than in the single agent arm, the survival benefit to patients receiving such combination chemotherapy was not determined and more effective chemotherapy regimens are required.     

Radiotherapy combined with cis-diammine-dichloro platinum (II) plus vindesine in the treatment of non-small cell lung cancer: a comparison with treatment by radiation alone

The effect of CDDP + VDS has been evaluated in 39 cases of non-small cell lung cancer, compared with those treated with radiation alone. Nineteen cases consisted of a combined radiation and chemotherapy group, while twenty cases were classed a the radiation therapy only group. CDDP was given at a dosage of 60 to 110 mg/m2 every 4 weeks, and VDS at a dosage of 3 mg/m2 3 times weekly. Radiation was given at a fraction dose of 1.5 to 2 Gy 5 times per week with a mean total dose of 56 Gy in the radiation only group, and 50 Gy in the combined therapy group. There were no significant difference in both the response rate and the survival time between the two groups. This suggests that combined chemotherapy was not effective for the treatment of non-small cell lung cancer.     

An early phase II trial combining cisplatin, carboplatin and vindesine in patients with inoperable non-small cell lung cancer

We conducted an early phase II trial of advanced non-small cell lung cancer (NSCLC) to evaluate the response efficacy of a combination of cisplatin (CDDP), carboplatin (CBDCA) and vindesine (VDS). The twenty-four patients in the study had had no previous treatment. CDDP (15 mg/m2), CBDCA (200 mg/m2) and VDS (3 mg/m2) were administered on Day 1, CDDP (15 mg/m2) was administered on Days 2-5, and VDS (3 mg/m2) was administered on Day 8. We observed 9 partial responses (PR), with a total response rate of 39%. The overall median survival was 72 weeks, and the 1-year survival rate was 57%. Major toxicities were hematologic; leukopenia of grades 3 and 4 occurred in 25% patients, and thrombocytopenia occurred in 21%. Therefore, the combination of CBDCA with CDDP and VDS chemotherapy was effective against inoperable NSCLC with tolerable toxicities and a favorable median survival time.     

Chemosensitivity testing of human lung cancer tissues using the succinate dehydrogenase inhibition test

We examined the chemosensitivity of 57 primary lung cancer specimens to 9 antitumor drugs, using the succinate dehydrogenase inhibition (SDI) test. Average succinate dehydrogenase (SD) activity was reduced to less than 50% by cis-diaminedichloroplatinum (II) (DDP), cyclophosphamide (CPA), carboquone (CQ), mitomycin C (MMC) and adriamycin (ADM). The lung cancer cells were relatively resistant to pepleomycin (PEP), 5-fluorouracil (5 FU), vincristine (VCR) and vindesine (VDS). Small cell lung cancers, or early stage lung cancers, tended to be more sensitive to these antitumor drugs. However, differences in sensitivity with respect to either histology, staging or degree of differentiation were not statistically significant. Correlation of SD activity between 2 drugs was high among those which inhibit DNA synthesis (DDP, CPA, CQ or MMC), or between VCR and VDS (inhibitor of mitosis), however, the correlation between VDS and CPA, CQ or DDP was weak. The SDI test is a simple in vitro method readily available to aid in selecting drugs to treat patients with lung cancer.     

Combination chemotherapy of ifosfamide, cisplatin and vindesine for non-small cell lung cancer

Twenty patients with advanced non-small cell lung cancer were treated with a combination chemotherapy consisting of ifosfamide (IFX), cisplatin (CDDP) and vindesine (VDS). The treatment schedule was IFX 1.3 g/m2 i.v., on days 1-5, CDDP 20 mg/m2 i.v., on days 1-5, and VDS 3 mg/m2 i.v., on days 1 & 8, and, in principle, the regimen was repeated every 4 weeks. Of 19 evaluable patients, there were 1 CR, 7 PR, 10 NC and 1 PD, with an overall response rate of 42.1%. The median duration of responses was 7.45 months, and the median survival time of all patients was 13.2 months. The major toxicities occurring were hematologic toxicity, alopecia, gastrointestinal toxicity and peripheral neuropathy. Hematologic toxicity was severe and was judged to be dose limiting, but clinically manageable. These results indicate that this combination chemotherapy is active against non-small cell lung cancer and deserves further studies.     

A comparative randomized phase II study of CDDP, CDDP-carboquone (CQ) and CDDP-etoposide as second-line chemotherapy in small cell lung cancer (SCLC)

51 SCLC patients who had received prior chemotherapies and had measurable lesions were randomized to CDDP, CDDP-CQ, and CDDP-etoposide treatment group. Prior chemotherapies of 49 complete cases were AVA (ADM, VCR, ACNU; 16 cases), TAVA (THP-ADM, VCR, ACNU; 17 cases), CAV (CPA, ADM, VCR; 4 cases) and others. The median period of 49 cases from prior chemotherapy to this chemotherapy was 4 weeks. In the CDDP alone group, CDDP was given at a dose of 80 approximately 100 mg/m2/4-5 weeks on Day 1, and in CDDP-CQ treatment group, patients were given the same dose of CDDP and CQ 6 mg/body on Day 1, 2. In CDDP-etoposide treatment group, the same doses of CDDP and etoposide 60 mg/m2 Day 1-5 (Total 300 mg/m2) were given. Response rate of the CDDP alone group was 6.7% (PR 1/total 15), that of CDDP-CQ group was 6.3% (PR 1/total 16), and in CDDP-etoposide group it was 16.7% (PR 3/total 18). In CDDP-CQ treatment, the main side effect was strong hematotoxicity (WBC; Grade 3, 5 patients, Grade 4, 2 Pl: Grade 3, 5 Grade 4, 3), and main hematotoxicity of CDDP-etoposide was leukopenia (W BC; Grade 3, 4 patients, Grade 4, 2 Pl; Grade 4, 1). In these patients, it was thought that CDDP was not useful in second chemotherapy, as not only CDDP alone but also the combination with CQ or etoposide.     

Combination chemotherapy of advanced transitional cell carcinoma with cis-platinum, cyclophosphamide, adriamycin and 5-fluorouracil (CISCAF)

Ten patients with advanced transitional cell carcinoma were treated with the combination chemotherapy (CISCAF) consisting of cis-platinum (CDDP), cyclophosphamide (CPM), adriamycin (ADM) and 5-fluorouracil (5-FU). There were 8 males and 2 females with a median age of 57 years (range 33-76). Prior to this chemotherapy, all primary lesions were resected surgically; one patient received irradiation, one interferon. CDDP (15 mg/m2) with mannitol diuresis and ADM (7 mg/m2) were given daily for 5 days. CPM (200-300 mg/m2) was given on day one, and 5-FU (200-300 mg/m2) on day 2. Courses were repeated every 3-4 weeks for 3 courses and later every 2 months. All patients were evaluable for toxicity and 9 for response. There were 3 (33%) partial and 2 minor responses. Survival difference between responders (PR + MR) vs non-responders (NC + PD) was significant during the 30-120 days of observation, but not significant throughout the whole period (generalized Wilcoxon test). The overall toxicity due to chemotherapy was generally mild, except for one irreversible nephrotoxicity and one gastric hemorrhage treated surgically.     

Development of platinum analogues for the treatment of lung cancer]

A number of platinum compounds have been synthesized and screened on the basis of structure-activity strategy. In Japan, clinical trials of three analogues (NK-121, DWA-2114R and 254-S) have been undertaken. NK-121, which have the same leaving group as carboplatin, the dose limiting factor (DLF) was leukopenia, while renal toxicity was extremely mild. DWA-2114R, also with the same leaving group, was less nephrotoxic than CDDP or less marrow toxic than CBDCA. DLF was also leukopenia. Phase II study revealed 29% and 12% response rates for small cell carcinoma (SCLC) and non-small cell carcinoma (NSCLC), respectively. In 254-S which has the same carrier ligand (NH2) as CDDP and CBDCA. DLF was thrombocytopenia with mild nephrotoxicity. Response rates of 41% and 21% were obtained for SCLC and NSCLC, respectively. In a randomized study comparing 254-S plus VDS with CDDP plus VDS, equivalent response rate and milder toxicity were observed for the 254-S group. Since highly active agents other than platinum compounds have been currently evaluated for the cases of lung cancer, preclinical screening for substantially active compounds is essential in developing new platinum analogues.     

Phase II study of cis-diamminedichloroplatinum in patients with non-small cell lung cancer

A phase II study of cis-diamminedichloroplatinum (CDDP, 80 mg/m2, every 3 weeks) was performed in patients with non-small cell lung cancer (NSCLC). The overall response rate to CDDP was 14% (6/42). In patients without prior chemotherapy, the response rate was 20% (2/10), and in patients with prior chemotherapy, the response rate was 13% (4/31). The major side effect was gastrointestinal toxicity. It was concluded that CDDP at a dose of 80 mg/m2 every 3 weeks is effective against NSCLC.     

New interesting chemotherapeutic regimens in advanced gastric cancer]

We have made over view of new chemotherapeutic regimen for treatment of advanced gastric cancer 5-FU + MMC, FT + MMC and UFT + MMC therapy have been used widely for treatment of advanced gastric cancer as chemotherapeutic regimens in Japan. These regimens did not shown made than 25% in response rate as antitumor effect. Since development of CDDP, FP (5-FU + CDDP), FAP (5-FU + ADM + CDDP) and EAP (Etoposide + ADM + CDDP) is becoming gradually very important regimen for treatment of advanced stomach cancer patients. Recently, we have studied EAP therapy on 50 cases of advanced gastric cancer from January 1988 to September 1989. ADM 20 mg/m2, CDDP 40 mg/m2 and Etoposide 100 mg/m2 were administered on day 1 and 7, 2 and 8, and 4, 5 and 6, respectively, with not less than 2 courses every 3 to 4 weeks. The rate of effectiveness were obtained 43.8% with a confidence interval 95% of 30-58%. Median survival time was only 5.1 months for EAP therapy, which was highly effective but led to no prolonged survival period. Thus it is thought that good control of leukopenia, a dose-limiting factor remains to be examined. Biochemical modulation of 5-FU using such as MTX + LV and CDDP + LV (leucovorin) now under studying in the nation wide in Japan, so far it is getting better results.     

维拉帕米联合化疗对胆管癌QBC939细胞株的抑制作用

目的 探讨维拉帕米(VER)联合化疗药物对胆管癌细胞株增生的抑制作用及其机制.方法 应用四甲基偶氮唑蓝(MTF)法检测VER、多柔比星(ADM)、丝裂霉素(MMC)、长春地辛(VDS)及VER分别联合ADM、MMC、VDS对胆管癌细胞株QBC939存活率的影响.流式细胞术(FCM)观察上述各组细胞生长周期及凋亡率的变化.免疫组织化学检测胆管癌细胞株QBC939细胞多药耐药P糖蛋白(P-gp)的表达.通过FCM观察胆管癌细胞株QBC939细胞内ADM的变化.结果 ADM、MMC、VDS对胆管癌细胞株QBC939的抑制率分别为48.84%、44.19%、45.76%,VER分别联合ADM、MMC、VDS对胆管癌细胞株QBC939的抑制率分别显著提高至64.37%、52.68%、65.90%.凋亡率也由11.37%、7.25%、9.04%提高为20.66%、14.18%、21.91%.细胞周期分布显示,加用VER对ADM和MMC组各个周期影响不明显,而VDS组阻滞于G2/M期的细胞明显增多.胆管癌细胞株QBC939细胞P-gp的表达率为38.00%.与ADM单独作用相比,联合VER后细胞内ADM的含量有一定增加.结论 VER可增加化疗药对胆管癌QBC939细胞株的抑制作用,增强胆管癌细胞对化疗药物的敏感性.     

Inhibition of colony formation of drug-resistant human tumor cell lines by combinations of interleukin-2-activated killer cells and antitumor drugs

The cytotoxicity of interleukin-2-activated killer (LAK) cells with or without anticancer drugs against cell lines with acquired drug resistance was evaluated in vitro by colony assay. Human non-small cell lung cancer cell lines, PC-9 and PC-14, human leukemia cell line, K-562, and their sublines resistant to cisplatin (CDDP), PC-9/CDDP and PC-14/CDDP, and to adriamycin (ADM), K-562/ADM, were used as target cells. PC-9/CDDP demonstrated a marked increase in susceptibility to killing by both peripheral blood lymphocytes (PBL) and LAK cells, as compared to the parental cell line, PC-9. The cytotoxicity of PBL and LAK cells against PC-14/CDDP and K-562/ADM was similar to that against their parental cell lines. Moreover, the combination of LAK and CDDP had a synergistic effect on PC-14 and PC-14/CDDP.     

Kinetic Analysis of Combination Effect of Navelbine (KW-2307) with Cisplatin against Human Lung Adenocarcinoma PC-12 Cells in Culture

The combination effect of navelbine (NVB, KW-2307), a newly synthesized vinca alkaloid, and cisplatin (CDDP) was compared with that of vindesine (VDS) and CDDP using human lung adenocarcinoma PC-12 cells. The growth-inhibitory activity of NVB or VDS was time-dependent, whereas that of CDDP was AUC (area under the curve)-dependent. When NVB or VDS was used in combination with CDDP simultaneously for 24 h, antagonism was observed in terms of growth-inhibitory activity. However, additive combination effect was observed when NVB or VDS treatment was followed by CDDP treatment. On this treatment schedule, a synergistic combination effect was observed in terms of the cell-killing activity assessed by colony formation assay. The growth-inhibitory activity of NVB or VDS was detected 24 h after the treatment, whereas that of CDDP became significant 72 h after the treatment. NVB and VDS caused cell accumulation in G2M phase at 10 times their IC⁸⁰ values, and cells with less than diploid DNA content were detected after 24 h at IC⁸⁰. CDDP caused accumulation of cells in S phase, and the effect became detectable 16 h after the treatment. The DNA histogram of cells treated with NVB or VDS in combination with CDDP was a superposition of those of cells treated with each drug alone. Significant differences in the characteristics of anticellular activity were not detected between NVB and VDS, although NVB inhibited cell growth at a slightly lower concentration than VDS at the short exposure time of 1–8 h.     

A phase I/II trial of cisplatin, docetaxel and ifosfamide in advanced or recurrent non-small cell lung cancer

This trial was initiated to evaluate the toxicity and activity of combination chemotherapy employing cisplatin (CDDP), docetaxel (DCT) and ifosfamide (IFX) in non-small cell lung cancer (NSCLC), and to determine the maximum tolerated dose (MTD) of IFX. Chemotherapy-naive patients with advanced or recurrent NSCLC received 60 mg/m(2) DCT followed after a 3-h interval by 60 mg/m(2) CDDP on chemotherapy day 1, and IFX at an escalating dose with mesna protection on days 2-4. The chemotherapy was repeated every 3 weeks. Granulocyte colony-stimulating factor (GCSF) was administered in the event of grade 3 leukopenia/neutropenia. The patients tolerated the treatment well up to level 4 of IFX dosing 1.5 g/day, but not the IFX dose at level 6 (2.0 g/day). Additional patients were enrolled in level 5 (IFX 1.7 g/day) to evaluate the toxicity of the drugs around the MTD. Level 5 was also judged as having exceeded the MTD, with febrile neutropenia and hepatic toxicity being observed as the dose-limiting toxicities. No toxicity-related deaths occurred. The majority of the chemotherapy courses were supported by GCSF administration. A total of 33 eligible patients were entered into the trial; the overall response rate was 10/33 or 30% among all eligible cases, and the rate for patients treated with the MTD or higher (levels 4-6) was 8/24, or 33% (90% confidence limit: 18-52%). The MTD of IFX was 1.5 g/m(2) administered for 3 days in this triplet combination. The clinical activity does not seem to justify the toxicity profile.     

Chemotherapy of invasive bladder cancer

This article is a review of the results of systemic chemotherapy for invasive bladder cancer. Transitional cell carcinoma of the urinary tract including the urinary bladder, renal pelvis and ureter has been moderately responsive to chemotherapy. Many chemotherapeutic agents have been studied singly or in combination. Until about 10 years ago, adriamycin (ADM) was the most studied agent for treatment of invasive bladder cancer. However, the results of single agents and combination with ADM have been disappointing; the overall response rate was approximately 20%. With the introduction of cisplatin (CDDP), the efficacy of chemotherapy for invasive bladder cancer has improved significantly. As single agents, CDDP has a response rate of 30 % in 320 cases, methotrexate (MTX), 29% in 236 cases, ADM, 17% in 248 cases, vinblastine (VBL), 16% in 38 cases, and mitomycin C, 13% in 42 cases. Presently the most important agents in the treatment of this disease are CDDP and MTX, and the next most useful agents are ADM and VBL. Recent data from limited trials in patients with advanced bladder cancer suggest that combination chemotherapy regimens with these agents induces a high percentage of complete remissions (CR), an overall response rate between 50% and 70%, and a median response duration of longer than 6 months. Most active combination regimens are M-VAC (CDDP + MTX + ADM + VBL), CMV (CDDP + MTX + VBL), CM (CDDP + MTX) and CISCA (CDDP + ADM + cyclophosphamide). These combination regimens with M-VAC, CMV, CM and CISCA show a response rate of 57%, 57%, 46% and 46%, respectively. However, these drugs have a substantial toxicity and their combination has still been regarded as too hazardous. The attainment of CR in 20% to 40% of cases given these combination regimens has led to adjuvant and neoadjuvant chemotherapy.     

Cisplatin, ifosfamide and vindesine in the chemotherapy of squamous cell carcinoma of the lung

Thirty-one patients with inoperable squamous cell carcinoma of the lung were treated with a combination of cis-platin (CDDP, 100 mg/m2 day 1), ifosfamide (IFX, 2 g/m2 day 1, 2, 3; with mesna) and vindesine (VDS, 3 mg/m2 day 1). The overall response rate (PR) was 71.0% with 22 partial responses. The median duration of response was 180 days. The median duration to show 50% decrease was 29 days. Myelosuppression and renal toxicity were severe. We concluded that the CIV regimen against squamous cell carcinoma of the lung was more effective yet more toxic than the other regimen containing CDDP and that candidates for this therapy must be carefully chosen.     

Comparison of methods for evaluating the nephrotoxicity of cisplatin

The BUN, serum creatinine, creatinine clearance and the urinary excretion of leucine aminopeptidase (LAP), alkaline phosphatase (ALP), beta 2-microglobulin (beta-m), and N-acetyl-beta-glucosaminidase (NAG), were measured in 21 gynecological cancer patients treated with CAPF (CPA + ADM + CDDP + 5-FU) to evaluate the sensitivity of these indices to renal tubular damage. After receiving CDDP almost all patients displayed an increase in excretion of beta-m but no urinary enzyme activities. However, NAG index (NAG activity/urinary creatinine) rose markedly in all patients. We concluded that NAG index is a valuable method in providing sensitive indices for detecting renal tubular damage caused by CDDP.     

Quantitative estimation of the thermal dose-modifying factor for cis-diamminedichloroplatinum (CDDP) in tumour-bearing dogs.

A statistical method for estimating clinical toxicity was used to determine a theoretical isoeffect dose-modifying factor for dogs with disseminated or refractory neoplasia treated with cis-diammine dichloroplatinum (II) plus whole-body hyperthermia or CDDP alone. CDDP was administered every 3 weeks with vigorous saline hydration to 54 dogs (CDDP alone n = 21, CDDP/WBH n = 33) that were eligible for entry into this non-randomized study. CDDP was administered during the plateau phase of WBH in dogs receiving combined therapy. Acute toxicity included myelosuppression (CDDP n = 7; CDDP/WBH n = 5), nephrotoxicity (CDDP n = 1, CDDP/WBH n = 1) and respiratory distress (CDDP/WBH n = 2). Eight dogs experienced chronic renal dysfunction as a result of CDDP (n = 2) or CDDP/WBH (n = 6). A theoretical thermal dose-modifying factor was determined for both acute and cumulative toxicity by comparing the maximum tolerated dose of each treatment group. The maximum tolerated dose (MTD) of CDDP +/- WBH was defined as that dose producing a 50% incidence of moderate acute toxicity or acute plus mild chronic toxicity as estimated from logistic regression analysis of the toxicity data. The MTD (+/- .standard error) of CDDP/WBH for acute toxicity only was 54.6 (4.3) mg/M2 and for CDDP alone the MTD was 73.6 (40) mg/M2. Thus, the isoeffect dose-modifying factor for acute toxicity was 1.35 (0.12). The MTD (SE) of CDDP/WBH for cumulative toxicity (acute plus chronic toxicity) was 46.4 (2.7) mg/M2 and for CDDP alone waas 70.0 (2.9) mg/M2. The isoeffect dose-modifying factor for total cumulative toxicity was 1.5 (0.1).(ABSTRACT TRUNCATED AT 250 WORDS)     

Current perspectives in the management of non-small cell lung cancer

Unfortunately, unlike small cell lung cancer, clinical trials of chemotherapy for the treatment of non-small cell lung cancer (NSCLC) have not consistently demonstrated a clinical benefit. However, recent studies have indicated some progress in the development of drug combinations using several active antineoplastic agents with no overlapping toxicity, and, in recent years, clinical trials of combination chemotherapy with such agents as VDS and CDDP have consistently produced response rates of 40 approximately 50%. In this review, we are focusing on the details of updated treatment schedules of combination chemotherapy against NSCLC.