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.     

不同化疗方案治疗Ⅲ～Ⅳ期非小细胞肺癌的近期疗效观察

 目的　观察比较MVP(丝裂霉素、长春地辛、顺铂),MIC(丝裂霉素、异环磷酰胺、顺铂)和MNP(丝裂霉素、去甲长春碱、顺铂)联合化疗方案治疗Ⅲ～Ⅳ期非小细胞肺癌(NSCLC)的近期疗效和耐受性。方法　统计分析103例接受联合化疗的Ⅲ～Ⅳ期NSCLC,MVP组36例、MIC组30例,MNP组37例。结果　MVP组有效率30.6%,MIC组有效率33.3%、MNP组有效率48.6%,三组间疗效无显著性差异(P＞0.05)。主要毒副反应为骨髓抑制和胃肠道反应。结论　MVP、MIC和MNP方案治疗Ⅲ～Ⅳ期NSCLC疗效肯定,毒性可耐受,可以作为其一线治疗方案。     

Phase II studies of a single agent and a cis-platinum-based two-drug combination in patients with non-small cell lung cancer

Phase II studies of single agent and CDDP-based two drug combination were performed in 189 patients with inoperable non-small cell lung cancer. Six drug regimens were performed: CDDP alone, VDS alone, Epi-ADM alone, CDDP + VDS, CDDP + CPA, CDDP + ADM. The response rates were 15.4% (6/39) with CDDP alone, 8.0% (2/25) with VDS alone, 6.1% (2/33) with Epi-ADM alone, 26.7% (8/30) with CDDP + VDS, 14.3% (4/28) with CDDP + CPA, 17.6% (6/34) with CDDP + ADM and one CR was performed with CDDP + ADM. In patients with no prior chemotherapy, the response rates were 20.0% (6/30), 11.8% (2/17), 12.5% (2/16), 26.7% (8/30), 16.0% (4/25) and 25.0% (3/12), respectively. The median survival times were 25, 27, 23, 33, 25, and 45 weeks, respectively. The efficacy of CDDP in non-small cell lung cancer patients was re-confirmed, and that of CDDP + VDS, CDDP + ADM was suggested. No death due to toxicity occurred and toxicity was generally tolerable.     

Experimental chemotherapy for xenograft cell lines of human bile duct and gall bladder cancers in nude mice.

Most biliary tract cancers are advanced and inoperable when first diagnosed. Even if surgery can be performed, the postsurgical prognosis of these diseases is poor. In the present study, we investigated effective chemotherapies for a human bile duct cancer xenograft cell line (undifferentiated carcinoma, BDC-SN) and a gall bladder cancer xenograft cell line (well-differentiated adenocarcinoma, GBC-GN), which were transplanted into nude mice. Eight anticancer agents (CDDP, 5-FU, VDS, MMC, ADR, EPIR, CQ, and VP-16) and their various combinations were evaluated at 2-4 times the clinical dose. When used singly, CDDP, 5-FU, and VDS were effective against BDC-SN, and only CDDP was effective against GBC-GN. Among the various 2-agent combinations, CDDP + 5-FU was the most effective against both BDC-SN and GBC-GN. However, 3-agent combinations consisting of CDDP + 5-FU + another agent were less effective than the CDDP + 5-FU double regimen and caused significant loss of weight as well as high mortality. These results suggest that CDDP + 5-FU may be the most useful regimen against biliary tract cancers in clinical application.     

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.     

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.     

PGC方案诱导化疗后同步放化疗治疗Ⅲ~ⅣA期鼻咽癌的Ⅱ期单中心前瞻性临床研究

目的 评价脂质体紫杉醇、吉西他滨、卡铂三药联合的诱导化疗（PGC方案）序贯同步放化疗治疗中晚期鼻咽癌患者的疗效及不良反应。方法 对初治Ⅲ~ⅣA期33例鼻咽癌患者, 给予2周期PGC方案新辅助化疗,序贯同步放化疗。诱导化疗方案：脂质体紫杉醇135 mg/m2+吉西他滨1 000 mg/m2+卡铂,血药浓度-时间曲线下面积（area under the curve,AUC）取5,第一天给药,每三周一次。第7周开始调强放射治疗同步化疗,卡铂AUC=5, 每三周一次。结果 在PGC诱导化疗两周期后评价：7例（21%）完全缓解（CR）,21例（64%）部分缓解（PR）,4例（12%）稳定（SD）,1例（3%）进展（多发性肺转移）。放疗完成3月后评价,28（85%）例CR、4（12%）例PR、1例（3% ）PD。1年总生存率100%,1年无病生存率91%。主要不良反应包括白细胞下降,血小板减少反应,肝功能损害,均可逆转。结论 PGC三药方案诱导化疗序贯同步放化疗治疗Ⅲ~ⅣA期鼻咽癌疗效较好,不良反应可耐受。     

以异环磷酰胺、顺铂、长春地辛联合化疗为主综合治疗小细胞肺癌的疗效观察

目的　观察异环磷酰胺 (IFO)、顺铂 (DDP)、长春地辛 (VDS)联合化疗为主综合治疗小细胞肺癌的疗效及毒副反应。方法　 3 6例小细胞肺癌采用IFO 2 .0静滴连用 5天 ,MESNA 40 0mg于IFO后 0、4、8h静脉输注 ,VDS 5mg第 1、8两天静脉输注 ,DDP 40mg静脉滴注 ,连用 3天。 2 1天为一周期 ,2～ 4周期后给予放疗。之后再按原方案化疗 4～ 6周期止并评价疗效。结果　总有效率为 72 .2 %( 2 6/3 6) ,其中初治者 84.0 % ( 2 1/2 5 ) ,复治者 45 .5 % ( 5 /11) ;1年生存率为 75 .0 % ,3年生存率为 3 6.1%。主要毒副反应为骨髓抑制。结论　以异环磷酰胺、顺铂、长春地辛联合化疗为主的综合治疗小细胞肺癌能有效地提高患者近期和远期疗效 ,毒副反应能够耐受。     

宫颈癌术前新辅助化疗20例疗效观察

目的:研究巨块型宫颈癌术前新辅助化疗(neoadjuvant chemotherapy,NACT)的疗效.方法:2000年1月～2004年2月收治的巨块型宫颈癌20例,采用化疗方案为:顺铂(DDP)20mg/m2,静点,第1～5天;博莱霉素(BLM)10mg/m2,肌注或静点,第1、3、5天;羟基喜树碱(HCPT)6～10mg,静点,第1～5天.化疗后19例行广泛全子宫加盆腔淋巴结清扫术.结果:本组20例巨块型宫颈癌应用NACT治疗,显效率(CR PR)70%,有效率(CR PR MR)95%.其中2例局部肿物基本消失,宫颈仅呈糜烂状,效果甚为理想.结论:术前采用DDP BLM HCPT方案化疗,可使宫颈局部肿块缩小或消失,从而提高手术成功率,延长患者的生存期.     

Effects of combined therapy with irradiation, cisplatin and vindesine in lymph node recurrence of esophageal cancer

The effects of combined therapy with irradiation, cisplatin and vindesine for lymph node recurrence of esophageal cancer was studied. The subjects were 95 patients with lymph node recurrence, who were divided into the following four treatment groups: Group I: Radiotherapy alone (R) (n = 31); Group II: cisplatin (CDDP) alone (n = 18); Group III: R + CDDP(n = 9); Group IV: R + CDDP + VDS (n = 10). The response rate (CR + PR) of Groups III and IV was 66.7% and 100%, respectively, which was significantly more favorable than 11.1% of Group II. The survival duration after recurrence was prolonged in the order of Group IV, Group III, Group II and Group I. In conclusion, combination therapy using R, CDDP and VDS will be effective for lymph node recurrence of esophageal cancer.     

Preclinical evaluation of several cisplatinum analogs against human esophageal carcinoma by subrenal capsule assay

The antitumor activities of CDDP analogs (CBD-CA, NK-121, 254-S) were evaluated preclinically by subrenal capsule assay (SRCA) with cyclophosphamide pretreatment. In the fundamental study, the antitumor activities against serially transplanted human esophageal cancer xenograft (IMEs-1) were compared with subcutaneous transplantation assay in nude mice and SRCA. The antitumor activities in SRCA were similar to those of in nude mice assay system (CBDCA greater than CDDP greater than 254-S greater than NK-121). Thus SRCA was considered to be useful for the evaluation of the activities of these agents. The activities were also tested against 10 human esophageal tumors obtained clinically. The sensitivity rate of these agents were 50% in CDDP, 30% in CBDCA, 30% in NK-121, and 30% in 254-S, respectively. These analogs seemed to be less effective than CDDP. However, in two cases, analogs were active though CDDP were inactive. The results suggest that these analogs are useful for the cases in which CDDP can not be given due to the toxicities and also for outpatient use.     

A randomized comparative study of 254-S plus vindesine (VDS) vs. cisplatin (CDDP) plus VDS in patients with advanced non-small cell lung cancer (NSCLC)]

It has been shown in phase II studies that 254-S, a new anticancer platinum complex, is effective in the treatment of various cancers. In order to more objectively evaluate the clinical usefulness of this compound, a randomized comparative study of 254-S plus VDS vs. CDDP plus VDS was conducted in patients with advanced NSCLC. 254-S or CDDP was intravenously administered at 90 mg/m2, at least 2 times at 4-week intervals. VDS was intravenously administered at 3 mg/m2 on Days 1 and 8 of each treatment of 254-S or CDDP. Of 136 patients registered, 121 (64 of the 254-S/VDS group and 57 of the CDDP/VDS group) were evaluable for tumor response (complete cases). There was no significant intergroup difference in the tumor response rate (254-S/VDS group: 12.5% [8/64], CDDP/VDS group: 15.8% [9/57]), nor by cancer staging, histological type or survival. As for toxic effects, leukopenia was significantly less frequent in the 254-S/VDS group while thrombocytopenia was significantly less frequent in the CDDP/VDS group. Nephrotoxicity such as an elevation of BUN and a decrease in serum creatinine was significantly less frequent in the 254-S/VDS group in spite of the lower volume hydration performed. In addition, nausea and vomiting as well as anorexia were observed with significantly lower incidences in the 254-S/VDS group despite the less frequent anti-emetic treatment. Based on these results, it was concluded that combination treatment with 254-S and VDS is a safe and useful regimen for treatment of NSCLC, generating antitumor effects equivalent to the CDDP/VDS regimen.     

Combination chemotherapy of nicardipine and vindesine sulfate, cis-diammine dichloroplatinum (II) for patients with advanced esophageal carcinoma

Since calcium (Ca) antagonist enhances the antitumor effect of vinca alkaloid in vitro, The authors attempted to combine nicardipine (Ca antagonist) with vindesine sulfate (VDS) and cis-diammine dichloroplatinum (II)(CDDP) for treatment of two patients with advanced esophageal carcinoma who were considered to be resistant to two courses of combination chemotherapy of VDS and CDDP. In the first case nicardipine was given orally and for only one day at a dose of 60 mg followed by 40 mg two and a half hours later. Thirty minutes after 60 mg of nicardipine, 3 mg of VDS on day 1, and 50 mg of CDDP (repeated for 3 days) were given. The maximum plasma concentration of nicardipine was 834.0 mg/ml, and the patient showed a partial response. In the second case nicardipine was given intravenously at a dose of 10 mg/body/hour for 8 hours which was repeated for 3 days. The same dose of VDS and CDDP as the first case was started the second day. The maximum concentration of nicardipine was 254.3 ng/ml, and this patient did not show any response. These results may suggest that a sufficient plasma concentration of nicardipine would obtained some response even in solid tumors.     

Syndrome of inappropriate antidiuretic hormone secretion following cisplatinum and vindesine administration in a patient with squamous cell carcinoma of the lung

We report a patient with squamous cell carcinoma of bronchus who developed the syndrome of inappropriate antidiuretic hormone secretion (SIADH) after receiving cisplatinum (CDDP) and vindesine (VDS). The 75-year-old man developed right chest pain and was found to have a squamous cell carcinoma of bronchus (stage IIIA, T3N1M0). He was treated by CDDP and VDS. The serum sodium concentration decreased from 136 mEq/l to 120 mEq/l after drug administration. SIADH was diagnosed on the basis of hyponatremia with corresponding serum hypoosmolality and an inappropriately high urinary osmolality due to continued sodium excretion. In our case, SI-ADH was probably induced by CDDP or VDS. Fluid restriction and sodium supplement resulted in a progressive rise in the serum sodium level to 134 mEq/l in 4 days.     

国产异环磷酰胺、顺铂和长春酰胺联合用药治疗晚期肺癌

探讨国产异环磷酰胺为主的联合化疗方案治疗晚期肺癌的疗效及毒副作用。方法：４３例肺癌中非小细胞肺癌４０例,其中Ⅲ期２例,Ⅳ期３８例,小细胞肺癌３例。化疗方案为异环磷酰胺２．０ｇ静滴,顺铂３０ｍｇ静注,连用３天,长春酰胺４ｍｇ第１天静注,用尿路保护剂巯乙黄酸钠４００ｍｇ于异环磷酰胺后０、４、８ｈ输注,     

A phase II study of cisplatin and continuous infusion of vindesine in metastatic head and neck squamous cell cancer

The chemotherapeutic treatment of recurrent and/or metastatic squamous cell carcinoma (SCC) of the head and neck (H & N) has a very dismal prognosis, with survival usually not exceeding 1 year. Reported objective response rates vary between 3% and 70%. This difference appears largely attributable to the heterogeneity of the patient populations included in most published Phase II studies in H & N cancer. They usually include together initially metastatic, recurrent, and post primary treatment metastatic disease patients. These patients respond differently to chemotherapy. Because of this situation, we decided to study a more homogeneous patient population consisting of metastatic patients only. Cisplatin (CDDP) and vindesine (VDS) are active agents in H & N SCC. As VDS has a cycle-specific activity, the therapeutic index may be increased if it is administered in a continuous infusion (CI) schedule. Thirty-three patients with metastatic H & N (69% biopsy proven) were treated with a combination regimen including CDDP (100 mg/m2) day 1 and VDS 0.6 to 1 mg/m2 for 96 hours of CI. Thirty-one patients were evaluable for response: five had a complete response (CR; 16%) and 11 had a partial response (PR; 36%) with an overall rate response of 52% (95% confidence limit: 33% to 70%). Median duration of CR was 6.4 months (3 to 19 months) and 4.4 months for PR (3 to 6 months). A decrease in the leukocytes was the main toxicity encountered with this regimen. This combination regimen containing CDDP and CI VDS was well tolerated and active in H & N SCC. The incorporation of an active vinca-alkaloid in neoadjuvant regimens should be considered.     

Cisplatin,ifosfamide and vindesine in the chemotherapy of non-small-cell lung cancer: a combination phase II study

Summary A total of 47 patients with unresectable non-small-cell lung cancer were treated with a regimen consisting of cisplatin (CDDP, 100 mg/m²), ifosfamide (IFX, 2 g/m² × 3; with mesna) and vindesine (VDS, 3 mg/m²) (CIV). This regimen was given over a 3- or 5-week period. Among 40 completely evaluable patients, 19 partial responses (PRs) were observed, for a response rate of 47.5% (78.6% in squamous-cell carcinoma and 30.1% in adeno-and large-cell carcinoma); no complete responses (CRs) were obtained. The hematologic toxicity was not severe, but the renal toxicity was rather high; two patients developed acute renal failure and died of subsequent pancytopenia and sepsis. We concluded that the CIV regimen was more effective, especially against squamous-cell carcinoma, but more toxic than the combination of CDDP and VDS for non-small-cell lung cancer and that candidates for this therapy must be carefully chosen.     

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.     

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.     

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.