A randomized trial with various combinations of cis-platinum (CDDP), mitomycin C (MMC), peplomycin (PEP) and ftorafur (FT) in the treatment of non-small cell lung cancer

From March 1983 to February 1985, we treated 74 patients (pts) with inoperable non-small cell lung cancer. Twenty-seven pts with squamous cell carcinoma were randomized between regimen PMP (CDDP 60 mg/m2, d 1, MMC 6 mg/m2, d 3, d 10 and PEP 5 mg/m2, d 3-7) and regimen PM (CDDP 60 mg/m2, d 1 and MMC 6 mg/m2, d 3, d 10). Forty-seven pts with adenocarcinoma and large cell carcinoma were randomized between regimen PMF (CDDP 60 mg/m2, d 1, MMC 6 mg/m2, d 3, d 10 and FT 800 mg/body, d 3-21) and regimen PM. The response rates of evaluable cases (EC) were as follows: Squamous cell carcinoma; Regimen PMP 50% (1 CR + 4 PR/10 EC). Regimen PM 40% (4 PR/10 EC). Adenocarcinoma plus large cell carcinoma; Regimen PMF 13.6% (3 PR/22 EC). Regimen PM 11.1% (2 PR/18 EC). The median survival time (MST) was increased from 23 weeks in non-responders to 32 weeks in responders. However, the difference between the survival curves for responders and non-responders was not statistically significant. Of the toxic effects shown in all 74 registered pts, hematological (64.9%), gastrointestinal (60.8%) and renal (31.1%) toxicities were the common complications. We concluded that regimen PMP was more useful than regimen PM for pts with squamous cell carcinoma but that regimen PMF demonstrated no appreciable difference, compared with regimen PM for pts with adenocarcinoma and large cell carcinoma.     

Effects of the bronchial artery infusion of peplomycin (PEP) and mitomycin C (MMC) in lung cancer--comparison with single administration of PEP or MMC

Effects of BAI with PEP 30 mg+MMC 10 mg on 26 patients with lung cancer were evaluated in comparison with 34 cases treated with single PEP or MMC. Histopathological findings of the cases treated with PEP+MMC and PEP alone showed more effective results than that of MMC alone. The tumor decreased rate on the chest X-ray film of the cases treated with PEP+MMC was highest and the cavity formation was also typical in the cases with PEP+MMC and PEP alone. The side effects of the cases with PEP+MMC were able to reduce markedly to about 50% compared with single administration of PEP or MMC; however pulmonary fibrosis and necrotizing bronchitis were noted in 8%.     

Clinical effect of combination chemotherapy with peplomycin and mitomycin C (PM therapy) in recurrent uterine cervical cancer

Seventeen patients with recurrent uterine cervical cancer were treated with combination chemotherapy consisting of consecutive intravenous drip infusion of PEP 5 mg for 6 days and intravenous infusion of MMC 10 mg on the 6th day. Of twelve evaluable cases, 2 complete responses and 6 partial responses were obtained and the response rate was 67%. The median survival for responders was 61.3 weeks as compared with 28.0 weeks for non-responders. The initial clinical effect appeared after at least two courses. Pulmonary toxicity in the form of interstitial pneumonitis occurred in 8 cases (50%) including 2 cases of pulmonary fibrosis. This result suggests that PM therapy is a very useful treatment method for recurrent uterine cervical cancer which can be performed safely.     

Combination chemotherapy of 5-fluorouracil (5-FU), adriamycin (ADM), cis-diamminedichloroplatinum (II) (CDDP) and mitomycin C (MMC) (FAP.MMC) in advanced gastric cancer

Twenty patients with advanced gastric cancer were treated with FAP.MMC (5-FU 350 mg/m2 i.v. on days 1-3, ADM 40 mg/m2 i.v. on day 1, CDDP 20 mg/m2 i.v. on days 1-3, MMC 6 mg/m2 i.v. on day 1), administering 5-FU, ADM and CDDP every 4 weeks and MMC every 8 weeks. Fourteen patients were evaluable for responses. Four (29%) partial responses and two minor responses were observed. The median duration of partial response was 3.8 months (range 2.5-7 months). The median overall survival time was 5 months (range 1.5-15 months). Leukopenia was relatively severe, with a median WBC nadir of 1,300/mm3. Nausea and vomiting were frequent but moderate. However, these toxicities were clinically manageable. FAP.MMC was thus considered effective for advanced gastric cancer.     

Interstitial pneumonia developed after combination chemotherapy with (CDDP, VDS, MMC) and radiotherapy

Reported is a case of interstitial pneumonia that developed after CDDP, VDS, and MMC combination chemotherapy and radiotherapy. The patient, a 68-year-old male, had received chemotherapy three times, beginning with CDDP + VDS, followed by CDDP, VDS, and MMC, in that sequence, after which he was given radiotherapy. The interstitial pneumonia developed one day after a dose of 54 Gy. It is felt that MMC played the leading role and the radiation the inducing role in the development of his interstitial pneumonia.     

Clinical study of combination chemotherapy with mitomycin C, vindesine and cisplatin (MVP therapy) in advanced non-small cell lung cancer

Thirty-seven patients with inoperable non-small cell lung cancer were treated with the combination chemotherapy (MVP therapy) with mitomycin C (8 mg/m2), vindesine (3 mg/m2 X 2) and cisplatin (60 mg/m2). The partial responders were 13 cases (35%), and the median survival time was 271 days. In this study the cisplatin dose was less than in any other report of "MVP" therapy. But both the response rate and the median survival time did not differ from those reported elsewhere. The side effects (bone marrow suppression, renal toxicity, etc.) were mild, and did not prevent the continuance of this therapy. Thus, we could repeat more than 6 courses of "MVP" therapy for 8 patients. Nowadays, it is difficult to obtain complete responders with any chemotherapy for inoperable non-small cell lung cancer. To prolong lives of patients and maintain good quality of life, we recommend chemotherapy with low toxicity in often-repeatable courses.     

Combination chemotherapy with peplomycin, cis-platinum and mitomycin C in gynecologic cancer

Eight patients with gynecologic cancer (cervix: 6, corpus: 1 and vulva: 1) were treated with combination chemotherapy, PPM therapy consisting of continuously infused PEP 4mg/m2 days 1-5, CDDP 13 mg/m2 days 1-5, and MMC 3mg/m2 day 1. This was repeated every three to five weeks. Six of the eight patients were evaluable, two had a complete response and one had a partial response, for an overall response rate of 50%. Because of hematological toxicity, blood transfusion was carried out in four patients. Nephrotoxicity and pulmonary toxicity were slight. Nausea and vomiting were controlled with dexamethasone and domperidone. PPM therapy is considered to be an effective and useful combination chemotherapy for patients with gynecologic cancer.     

Effects of pepleomycin (PEP) infused through bronchial artery for lung cancer: in comparison with the cases of mitomycin (MMC) or carboquon (CQ)

(1) Therapeutic effects of bronchial artery infusion (BAI) of peplomycin (PEP), a derivative of bleomycin, were examined in the 13 patients with lung cancer. The effectiveness of PEP was compared with that of 59 patients treated with mitomycin (MMC) or carboquon (CQ). (2) In all cases treated with PEP, histopathological effects revealed to be more than grade IIa of Shimosato's criteria, which were more effective than that with MMC or CQ. (3) Histopathological changes of the metastatic lymph nodes were similar to that of the main tumor. (4) In the cases treated with PEP, tumor decreased rates shown in the chest X-ray films 2 weeks after BAI were lower than that with MMC or CQ. Cavity formation in the tumor was recognized in 62% of the cases treated with PEP. (5) Low fever lasting several days after administration of BAI and GI symptoms such as nausea and vomiting were main side effects, which were mild and not so serious.     

Combination chemotherapy with cis-dichlorodiammineplatinum (11) (CDDP) and bleomycin BLM in advanced esophageal carcinoma

Five patients with advanced carcinoma of the esophagus were treated with a combination chemotherapy employing CDDP and BLM. One cycle of chemotherapy consisted of CDDP, 50 mg/m2, on day 1 and BLM, 15 mg/patient on days, 1, 7 and 14. Two partial remission and 2 minor responses were obtained. Overall response rates, ths, were 80%. The most adverse effect was nausea. No significant elevation in the serum creatinine or BUN was recognized. Furthermore, the method of CDDP administration was studied on the serum level by 15 minutes' infusion and by 24 hours continuous infusion. The CDDP levels in the serum and tissue were determined by flameless atomic absorption spectrophotometry. The CDDP level in the serum by 15 minutes' infusion was higher than that by 24 hours continuous infusion. These results suggest that combination chemotherapy with CDDP and BLM may be a useful method for the treatment of advanced esophageal carcinoma.     

Clinical study of intraperitoneal chemotherapeutic perfusion (IPCP) of mitomycin C (MMC) and intraperitoneal administration of cisplatin

IPCP was performed in an attempt to control ascites production by malignant tumors, and its inhibitory effect on ascites production was studied. The subjects were 24 patients who underwent surgery at this department between April 1981 and April 1986, consisting of 19 cases of ovarian cancer, 3 cases of cancer of the uterine body, 1 case of retroperitoneal tumor, and 1 case of metastatic ovarian cancer. As the treatment at the time of laparotomy, 30 mg of MMC was dissolved in 300 ml of normal saline and intraperitoneally administered. After holding for 30 minutes, it was discharged by cleaning out the abdominal cavity with 3,000 ml of normal saline. Immediately before closure of the wound, (A): MMC 10 mg, OK-432 100 KE, neocarzinostatin 4,000 units, or (B): (A) + cisplatin 100mg, was intraperitoneally injected, and the wound was closed without washing out this anticancer cocktail after drainage of the abdominal cavity and abdominal wall. Among the present 24 cases, (A) was applied in 17 cases, and (B) in 7 cases. The inhibitory effect on ascites production was 87.5% or 21/24 cases, specifically 88.2% (15/17) in the (A) group and 85.7% (6/7) in the (B) group. There were no particular side effects.     

Neoadjuvant intraarterial chemotherapy with nedaplatin,peplomycin and mitomycin C for advanced cervical cancer

The aim of the present study was to examine the usefulness of neoadjuvant intraarterial chemotherapy (NAC) using nedaplatin as key drug to improve the prognosis in case of advanced cervical cancer. Twenty-five cases of advanced cervical cancer (15 cases of stage II with high risks, 10 of stage III, referred to as the 254-S group) treated by NAC using nedaplatin, mitomycin C and peplomycin were compared with 30 cases (22 cases of stage II with high risks, 8 of stage III, referred to as the CDDP group) treated using cisplatin and mitomycin C which is the conventional regimen, in terms of measurable response, pathological response, rate of lymph node metastasis, cumulative survival rate, side effects and relapse style. According to the evaluation by measurable responses, the response rate was 90% (CR 52%) in the 254-S group and 75% (CR 15%) in the CDDP group. For pathological response of the specimen, the CR rate was 16% in the 254-S group and 23% in the CDDP group. The rate of lymph node metastasis extracted surgically was 33% and 41%, respectively. The cumulative survival rate in the 254-S group was about 10% better than in the CDDP group, but no significant difference was found. Leucopenia of both groups was of the same grade. In the 254-S group, although thrombocytopenia was more critical than in the CDDP group, there was a slight tendency to kidney toxicity. The locoregional recurrence rate was 12% in the 254-S group and 30% in the CDDP group. The distant metastasis rate was 16% and 27%, respectively. Although neoadjuvant intraarterial chemotherapy using nedaplatin as a key drug was useful to improve the prognosis of advanced cervical cancer, measures against recurrence outside the pelvis and individualization of medical treatment were considered to lead to a further improvement of the prognosis.     

New combination chemotherapy for malignant melanoma--PAV(peplomycin, ACNU, VCR) therapy

A combination chemotherapy (PAV) consisting of peplomycin, ACNU and vincristine (VCR) was given to 30 patients with malignant melanoma and its therapeutic evaluation was performed. The objective response rate was 42.9% for the patients with stage IV metastatic lesions; three of 7 patients showed improvement. This regimen was particularly effective for both cutaneous and subcutaneous metastatic lesions. When PAV was applied as an adjuvant therapy to the operable cases with stage Ib and II, a five-year survival rate was 50% and the result was far better than that of operation alone. Our results in PAV regimen almost identical with those of DAV(DTIC, ACNU, and VCR) regimen as an adjuvant therapy. The result indicates that PAV regimen is useful for the treatment of malignant melanoma since toxic reactions were mild. Further studies are necessary to assess the efficacy of PAV regimen.     

Successful treatment of mediastinal seminoma with combination chemotherapy of cis-diamminedichloroplatinum (CDDP), vinblastine (VBL), and bleomycin (BLM)

Complete response (CR) has been achieved in a case of advanced mediastinal seminoma using PVB therapy (CDDP, VBL, BLM). A 21-year-old man visited our department with the complaint of superior vena cava syndrome. Chest X-ray film, ultrasonography and CT scan revealed a large anterior mediastinal mass. Histological proof of mediastinal seminoma was obtained by needle biopsy. The patient was treated with a combination chemotherapy, consisting of CDDP, VBL and BLM according to Einhorn's PVB regimen. After three courses of this regimen, complete disappearance of the tumor was obtained. The patient underwent further radiation treatment (Linac: 4,000 rad), as a salvage therapy, at the anterior mediastinum, and has since been doing well without any sign of recurrence for a follow-up period of nine months.     

Effects of bronchial artery infusion (B-AI) with single use of MMC after intravenous peplomycin (PEP) administration in lung cancer

Effects of BAI therapy on 86 cases of lung cancer were evaluated in three groups: single-use of MMC group after intravenous PEP administration (PEP (iv).MMC group), PEP and MMC combination use group (PEP + MMC group) and single use of MMC group. Tumor regression rate determined by chest X-ray film 2 or 3 weeks after BAI was highest in the PEP (iv).MMC group followed by the PEP + MMC and MMC group. Cavity formation was more typical in the group treated with PEP + MMC. Histopathological effects were best for the PEP + MMC group followed by those of the PEP (iv).MMC and MMC group. As for side effects, pulmonary fibrosis and necrotizing bronchitis were noted in 8% of the PEP + MMC group, but side effects in the other two groups were mild. In conclusion single use of MMC after intravenous PEP administration was found to be the best way to give BAI in these three groups.     

Phase II study of biweekly irinotecan and mitomycin C combination therapy in patients with fluoropyrimidine-resistant advanced colorectal cancer

PURPOSE: Experimental studies have shown that mitomycin C (MMC) acts synergistically with irinotecan. We evaluated the antitumor activity and toxicity of a combination of irinotecan and MMC in patients with metastatic colorectal cancer resistant to fluoropyrimidines. METHODS: Eligible patients had evidence of tumor progression while receiving fluoropyrimidine-based regimens or had disease recurrence within 6 months after the completion of adjuvant treatment with fluoropyrimidines. Irinotecan (150 mg/m(2)) and MMC (5 mg/m(2)) were administered on days 1 and 15 of a 28-day cycle. Treatment was repeated every 4 weeks. RESULTS: Among the 41 patients enrolled, 37 (90%) had received previous chemotherapy for metastatic disease, and 4 had received adjuvant chemotherapy alone. Objective responses were observed in 14 patients (34%, 95% confidence interval 20-49%). The median time to progression was 4.2 months, and the median survival time was 11.9 months. The study treatment was well tolerated; the median number of cycles received was four. Grade 3 or 4 neutropenia, the most common toxic effect, occurred in 20 patients (49%). Grade 3 or 4 thrombocytopenia occurred in four patients (10%) and grade 3 diarrhea in one patient. CONCLUSIONS: Our results suggest that irinotecan and MMC combination therapy is effective and well tolerated in patients with fluoropyrimidine-resistant metastatic colorectal cancer. Further clinical investigation of this regimen is warranted.     

Antitumor action of cis-dichlorodiammineplatinum(II) and the effectiveness of a combination with sarcolysine

Therapeutic properties of cis-dichlorodiammineplatinum (II) were studied on 12 strains of transplantable tumors and leukemias in mice. The compound is characterized by a wide spectrum of antitumor action. The greatest effect was gained in adenocarcinoma of the lage intestine (strain AKATOL), proventricular cancer (strain PRG) and adenocarcinoma of the mammary gland (strain Ca-755). The terms of survival in mice with leukemia (strain La and L-1210) and ascites hepatoma 22 are increased considerably. In some L-1210 animals the complete cure was noted. Cis-dichlorodiammineplatinum (II) may be effectively combined with sarcolysin. Much greater antitumor effect was obtained on 3 tumor strains (AKATOL, Ca-755 and sarcoma 37) with the combined therapy than with each drug used separately. The histological study of Ca-755 during chemotherapy indicated that immunocompetent cells of the organism play an important role in the mechanism of antitumor action of the platinum complex. This is manifested in the development of intensive lymphohistiocytic reaction around and inside the tumor. A damage to the convoluted tubules of the kidney and intestinal villi is one of the main adverse side-effects of the combination.