Leukemic transformation of polycythemia vera and essential thrombocythemia possibly associated with an alkylating agent.

BACKGROUND: Leukemic transformation of polycythemia vera (PV) and essential thrombocythemia (ET) is influenced by the therapeutic modalities used. A high incidence of leukemic transformation was found among patients with PV or ET treated with an alkylating agent, carboquone (CQ). The study was conducted to assess the causal relationship between CQ and leukemic transformation of PV and ET. METHOD: Twenty-seven patients with PV and 29 with ET diagnosed from January 1975 to August 1993 and whose clinical course could be followed comprised the members of this retrospective study. The patients were examined for the treatment administered, hematologic data, vascular complications, malignancies including leukemia, and eventual outcome. RESULTS: Eighteen patients with PV and 16 with ET were treated with CQ. The follow-up was 51-209 months for patients with PV and 28-176 months for those with ET. Three patients with PV (17% of those treated with CQ) and 5 with ET (31% of those treated with CQ) had subsequent transformation to acute leukemia. The median period until transformation of patients with PV was 94 months, whereas the median follow-up of patients without transformation was 146 months (P < 0.01). The median total days of CQ administration and the median total dose of CQ were 2022 days and 1226 mg, respectively, for the patients with transformation and 1051 days (P < 0.05) and 435 mg (P < 0.01), respectively, for those without transformation. Likewise, the median follow-ups for patients with ET with or without transformation were 130 and 90 months, respectively; the difference was insignificant. The median total days of CQ administration and the median total dose of CQ were 2075 days and 1019 mg, respectively, for patients with transformation and 571 days (P < 0.05) and 231 mg (P < 0.01), respectively, for those without transformation. These observations suggest that CQ may be involved in the leukemic transformation of PV and ET. The subtypes of leukemia transformed from PV corresponded to M2 in two patients and to M4 in one. All five patients with ET were found to have megakaryoblastic features at transformation, and three were diagnosed as having leukemic subtype M7. Chromosomal abnormalities were found in all five patients (two PV and three ET) examined after leukemic transformation, showing multiple and complex abnormalities in four. CONCLUSION: Showing that both the total days of CQ administration and the total dose of CQ were larger for patients with PV or ET whose disease subsequently transformed to leukemia, with this study, a possible causal role of CQ in leukemic transformation of PV and ET is suggested.

[Polycythemia vera terminating in myelodysplastic syndrome].

A 77-year-old male, who had been treated with carboquone and busulfan for polycythemia vera (PV), developed myelodysplastic syndrome (MDS) 8 years later. On admission the peripheral blood revealed pancytopenia, but blastoid cells were not noted. The bone marrow showed hypercellularity, and functional and morphological abnormalities in trilineages of hemocytes. Cytogenetic study showed complex abnormalities involving chromosomes 5 and 7. We diagnosed this case as secondary MDS to alkylating agents. He was treated with 1, 25 (OH)2 vitamin D3. However, it was not effective and the percentage of myeloblasts increased to 14.4%. In spite of supportive therapy, he died of sepsis due to urinary tract infection.

[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.

[Controlled study of MQF-OK therapy with FT and with UFT on various advanced gastrointestinal cancers. Hirosaki Cooperative Study Group of Cancer Chemotherapy].

Our cooperative study group carried out a controlled study of MQF-OK therapy with tegafur (FT) (group A) and with UFT (group B), a compound of FT and uracil in the molar ratio of 1:4, on various advanced gastrointestinal cancers. From January 1985 to May 1987, 91 patients were entered into this study, and 11 cases were ineligible for the protocol (11%). Fifty of 80 cases had advanced gastric cancer, 30 had pancreatic cancer or other cancers, such as colon cancer, and biliary tract cancer. They were divided into group A or B at random. There was no difference in the patient characteristics between group A and B. In gastric cancer, 23 of 50 cases were randomized into group A and 27 cases into group B. Two cases in group A (8.7%) and 7 cases in group B (25.9%) showed PR. The response rate of group B was better than that of group A, but the value of P by Kruskal-Wallis test was 0.27. Thirteen of the 30 other cancers were randomized into group A and 17 cases into group B. Three cases in group A and B, respectively, showed PR. There was no significant difference between the two groups in terms of antitumor effect, prolongation of life or side effects. In conclusion, it was suggested that the MQF-OK therapy with UFT was beneficial for the Remission Induction Therapy in advanced gastric cancer.

[Combination chemotherapy with adriamycin, carboquone and 5-Fu for bladder cancer].

We treated 25 bladder cancer patients with combined cytotoxic chemotherapy of adriamycin (10--20 mg/day administration on days 1, 2 and 3), carboquone (4 mg/day administration on day 1 of weeks 3, 4 and 5 and 5-Fu (200 mg/day for 5 weeks) or futraful suppositories (750 mg/day for 5 weeks) as one course. According to the Koyama - Saitoh criteria, CR + PR was observed in 4 (17.4%) of 23 patients excluding the 2 dropout patients. According to Karnofsky's criteria, an effect with chemotherapy was observed in 9 (39.1%) of the 23 patients. There was a relatively good response rate in a group of 12 patients with the superficial tumors as compared with a group of 11 patients with the deep tumors. There were no severe adverse reactions.

[Fundamental studies on intravesical instillation of carboquone for treatment of urinary bladder tumors--on the effects of intravesical instillation of carboquone in normal beagle dogs].

The effects of intravesical instillation of Carboquone at the clinically used doses of 5 and 10 mg on the normal mucosa of female beagle dogs was compared with that of 10 mg Mitomycin C used as the control drug. Intravesical instillation for 48 hours of 10 mg carboquone/20 ml phosphate buffer solution (PBS) after bilateral cutaneous uretrostomies produced severe inflammatory changes in all layers of the bladder wall. However, no secondary effects were observed in blood laboratory examinations or histological examinations of the whole organ after autopsy. Phosphate buffer solution produced no remarkable secondary effects in animals. Five milligrams carboquone per 20 ml PBS was instilled intravesically once a week for 3 weeks in normal animals. Cystoscopically , the bladder mucosa recovered normally. Blood laboratory examinations showed no abnormal results, but the bladder epithelium had regenerative epithelial hyperplasia and slightly inflammatory changes in the submucosal layers. Two of the three control animals given instillation of 10 mg of Mitomycin C/20 ml PBS had slight leucopenia at 7 days after the last intravesical instillation, but leucocyte count was normal at the end of the experiment. Cystoscopic and histological examination of the epithelium of the urinary bladder revealed severe inflammatory changes in 2 of the 3 animals.

[Clinical study on combination chemotherapy of primary liver cancer].

Three regimens were comparatively studied by a randomized trial in 95 patients with hepatic, biliary or pancreatic carcinomas: Group 1; Futraful (FT) alone, Group 2; FT plus cyclophosphamide (Ex), and Group 3; FT plus Carboquone (CQ). There was no difference in overall response rate among the three groups, evaluated by three valuables, i.e., improvement of subjective symptoms, improvement of laboratory examinations, and regression of the tumor. Group 2 demonstrated a favorable result in regression of the tumor as compared with other groups. In cases where the improvements of subjective symptoms and laboratory examinations were observed, the survival duration was prolonged, but in cases of the tumor regression, the survival was not prolonged. The improved survival rate was observed in Group 1, but neither in group 2 nor 3. There was no difference in the frequency of hematotoxicity among three groups (the frequency was as low as 3.4-8.8%). The frequency of side effect in subjective symptoms was 22% for the Group 1, 68% for the Group 2, and 62% for the Group 3, respectively.

[Study of combination chemotherapy with cytosine arabinoside in the intravesical treatment of superficial bladder tumors].

The effect of instillation therapy using CA alone or in combination with MMC, NCS or CQ was examined in 111 patients (92 males and 19 females, aged 32-87 years old with an average age of 66 years) with multiple superficial bladder tumors. The response rate of 29 patients given CA 400 mg alone was 48.3%, that of 25 patients given combination therapy of CA 200 mg and MMC 20 mg was 84.0%, that of 28 patients given combination therapy of CA 200 mg and NCS 4,000 U was 71.4%, that of 22 patients given combination therapy of CA 200 mg and NCS 6,000 U was 95.5% and that of 7 patients given combination therapy of CA 200 mg and CQ 10 mg was 100%. The response rates of the patients given any of the combination therapies were higher than that of the patients given CA alone. But because MMC, NCS and CQ were not administered singly, combination therapy cannot be concluded to be superior to single therapy. There was little difference between the response rate of primary cases and that of follow up cases. The side effects were all symptoms of local irritation, and were not indicative of systemic damage. Side effects were seen in 3.4%, 71.4%, 40.0% and 3.6% of the patients given CA alone, CA + CQ combination therapy, CA + MMC combination therapy and CA + NCS (4,000) therapy, respectively, combination therapy of CA and CQ producing the highest percentage of side effects.

[Combination therapy of large amount of carboquone and OK-432 for unresectable lung cancer].

The combination of 1 KE/day of OK-432 (everyday) and 10 mg/day of Carboquone (once a week) had been administered for three weeks to 18 cases of the patients with unresectable lung cancer. The response rate was 50% in the patients whose diameters of tumors could be measured. These results might be provided by the fact that the large dose administration of Carboquone became possible with simultaneous administration of OK-432, which might have an activating effect of bone marrow function; consequently, original properties of alkylating agent could be utilized in this therapy. Leukopenia, (leukocyte counts: less than 3,000) was observed in 10 out of 18 cases (55.6%) at one week after administration of the drugs, and in all but one case leukopenia was recovered after 4 weeks of the administration. No other severe side effects were observed.

[Combined administration of futraful and esquinone for the treatment of advanced ovarian cancer].

Thirty-seven patients with advanced ovarian cancer were treated with futraful (FT-207) and esquinone (CQ). These patients had infiltrated tumors to the pelvic and peritoneal cavity and also distant metastasis, so they were not operated perfectly. There were evaluable 12 patients out of 37. FT-207 + CQ is an effective drug combination against advanced ovarian cancer with an overall response rete of 40.9%, a complete response rate of 4.5% (1/22), partial response rate of 36.4% (8/22), no change rate of 27.3% (6/22) and progressive rate of 31.8% (7/22). Patients with adenocarcinoma showed a response rate of 66.7% (8/12). According to the stage, the patients in stage III showed response rate of 50.0% (6/12), in stage IV showed a response rate of 37.5% (3/8). The total dose of FT-207 used in the study was 38.3g in the progressive disease group and 177.6 in the good response group. The group of long term administration of FT-207 and CQ included many patients with good response.

[Combination chemotherapy with peplomycin and carboquone (esquinon) for squamous cell carcinoma of the lung].

Eighteen previously untreated patients with squamous cell carcinoma of the lung were treated with a combination of a new bleomycin derivative, peplomycin and esquinon (PQ). One patient achieved a complete response (5.5%) and 5 patients a partial response (27.8%). Overall response rate was 33.3%. Median survival time of 6 patients with complete and partial response was 54 weeks and that of 12 patients with no change and progressive disease was 15 weeks. Toxicities included nausea and/or vomiting in 89%, fever in 61%, interstitial pneumonitis in 28% and leukopenia in 17%. PQ regimen appears to be effective in the treatment of squamous cell carcinoma of the lung.

[Combined chemotherapy of ovarian cancer with special reference to carboquone].

Carboquone (CQ) was administered to 20 patients with ovarian cancer as a main drug in the multiple chemotherapy. Picibanil and Futraful (FT-207) were medicated simultaneously. CQ was given 3 mg each, 2 times a week, up to total 30 mg intravenously or intraperitoneally. 1) The effect of CQ was evaluated in 6 cases. The response was good in 2 cases, fair in 3, and poor in 1. In the other 3 cases after surgery long-lasting remission suggested the effectiveness of this drug. 2) When compared with 43 cases of control group(historical control), apparent higher survival rate was observed until 3 years in this group. 3) Side effects were noted in 89% of the patients. In 5 patients CQ treatment was discontinued because of severe complications. These complications were more pronounced when it was administered intraperitoneally or combined with radiation.

Local therapy of carcinoma of the uterine cervix: part I.

One-hundred-fifteen patients with cervical cancer were treated by placing bleomycin, carbazilquinone (Carboquone), and 5-fluorouracil suppositories in contact with cancer lesions located in the vaginal portion of the uterus or by inserting them into the cervical canal, twice a week, one to 14 times. The cancer lesions disappeared form 17 to 33 patients with Stage 0 lesions and 9 of 42 with Stage IA lesions. The remaining lesions were principally found in the deep portion of the cervical glands and tended to decrease the more often the suppositories were applied. This led to the presumption that if this local therapy had been carried on longer it would have eradicated even the remaining lesions from the patients with Stage 0 and IA lesions. The optimal per administration dose of bleomycin appeared to be 30 mg. The use of Witepsol (Dynamit Nobel Aktiengesellschaft, F.R.G.) suppository base was accompanied by frequent adverse reactions to it, which hindered the local therapy from being repeated over long periods of time. An equal amount mixture of hydroxypropyl cellulose and carbomer (Carbopol 934) as the suppository base was accompanied by relatively less adverse reactions, which permitted the prolonged local therapy with the suppositories. A trace of bleomycin was also found in the ovaries, but it did not cause microscopically evident histologic changes, nor did it affect the menstrual cycle. If early cancer can be treated completely by local therapy, it will be useful for the younger patient with early cervical cancer.

Anticancer drug sensitivity in vitro in the bladder cancer cell line, KK-47 and prophylactic use of carbazilquinone and urokinase in bladder cancer.

Using colony formation technique and KK-47 cell line established from a human bladder transitional cell carcinoma, the effect of 6 anticancer drugs, thio-TEPA, Bleomycin, mitomycin C, carbazilquinone, Adriamycin and cis-Platinum, were compared. On the results of tests performed to establish the drug concentration required to achive a 50% inhibition of cell survival, carbazilquinone was chosen for the prevention of recurrences of bladder cancer. The two groups studied consisted of 56 patients (previously untreated groups) who were rendered free of tumours by surgical intervention and of 19 patients (thio-TEPA failures group) who had experienced a persistent recurrence of tumours after prophylactic thio-TEPA instillations and were presumed free of the recurrence of tumours after the next surgical intervention. The 2 groups were subjected to prophylactic combined intravesical instillation therapy with carbazilquinone and urokinase. In the previously untreated group, 6 of the 56 patients (10.7%) had a recurrence of tumours, and the recurrence rate after 21 months was 16.7%, using the actuarial method. In the thio-TEPA failures group, 12 of the 19 patients (63.2%) had a recurrence of tumours, a rate at 21 months of 76.1%. A considerable drop in the recurrence rate was obtained by the combined instillation therapy in the previously untreated group. The results in the thio-TEPA failures group suggested the presence of a cross-resistance between both alkylating agents, and of a persistent susceptibility to multifocal lesions. No bone marrow depression was observed but an episode of anaphylactic shock attributable to the use of carbazilquinone occurred in 1 out of a total 75 patients.

Interaction of antitumor agents including carboquone in sarcoma-180 system.

Combination effect of antitumor agents including carboquone was evaluated on the concept of pharmacological synergism and not therapeutic synergism in ascites sarcoma-180 system. Combinations of carboquone plus cyclophosphamide, doxorubicin, and Methotrexate in simultaneous administration and carboquone plus doxorubicin in alternate one provided synergism. Combination effect of agents was affected by the schedule of drug administration. Toxicity of carboquone in combination with many antitumor agents, generally, decreased in simultaneous administration. Approved agents in combination with carboquone in simultaneous administration were Mitomycin-C, daunorubicin, Actinomycin-d, vinblastine, vincristine, Ancytabine, and 6-mercaptopurine. Those in alternate administration were Actinomycin-D and vinblastine.