Masanori Sakurai

Prognostic factors in non-small cell lung cancer: multiregression analysis in the National Cancer Center Hospital (Japan)

SummaryA total of 190 patients with unresectable non-small cell lung cancer (NSCLC) were analyzed retrospectively using eight pretreatment and three treatment-related prognostic factors in terms of influence on survival. All the patients received chemotherapy with or without chest irradiation, according to the protocol of phase II or phase III trials of the National Cancer Center Hospital Tokyo between April 1980 and December 1985. The eight pretreatment factors selected were performance status, sex, stage, age, histology, and metastasis to brain, bone or, liver. Three treatment-related factors were radiation therapy to the primary site, response to chemotherapy, and treatment period, before or after clinical adminsitration of cis-diamminedichloroplatinum (II) (CDDP). Of the 190 patients, 71 (37.4%) were alive for more than 1 year, but only 17 patients (8.9%) survived 2 years after the initiation of chemotherapy. By univariate analysis, performance status 0–1, female, no metastasis to bone or liver, response to chemotherapy, and treatment period after CDDP were considered to be favorable prognostic factors. By multiregression analysis, performance status, sex, and treatment period after CDDP proved to be important factors for long-term survival. Consideration of these prognostic factors could enable the results of chemotherapy to be more accurately evaluated, and stratification of patients with advanced NSCLC based on performance status and sex before entry into a randomized controlled trial is recommended.

In vitro colony inhibition of carboplatin against stomach and lung cancer cell lines in comparison with cisplatin

SummaryThe effects of carboplatin and cisplatin on colony formation in stomach and lung cancer cell lines were examined and compared. The colony-inhibitory activity of carboplatin against stomach and lung cancer cell lines was similar to that of cisplatin when one-tenth of the peak plasma concentration of each drug was used (r=0.80). One of the four stomach cancer cell lines was sensitive to carboplatin although all the stomach cancer cell lines were resistant to cisplatin. Of the three small cell lung cancer cell lines tested, two were sensitive to both carboplatin and cisplatin; and only one cell line (N857) was resistant to cisplatin; all the non-small cell cancer cell lines tested were resistant to both drugs. On the basis of these preliminary results, we suggest that carboplatin has potential therapeutic activity against stomach cancer and should be evaluated carefully from this aspect.

Comparative study of the antitumor effect of two types of murine recombinant interferons, (β) and (γ), against B16-F10 melanoma

SummaryA comparative study of the antitumor effect of murine recombinant interferon(β) 〈Mu-rIFN(β)〉 and murine recombinant interferon(γ) 〈Mu-rIFN(γ)〉 on B16-F10 melanoma was conducted. Administration of Mu-rIFN(γ) i.p. into C57BL/6 mice on days 1 to 7 produced a higher suppressive effect than Mu-rIFN(β) both on the growth of s.c. implanted tumor and on the formation of artificial pulmonary metastasis. Pharmacokinetic study of Mu-rIFN(γ) demonstrated that high plasma levels were retained for a long time. In clonogenic assay, Mu-rIFN(γ) at 1000 units/ml showed about 80% inhibition of colonies of B16-F10 melanoma. However, Mu-rIFN(β) hardly inhibited the colonies, even at 1000 units/ml. Augmentation of natural killer (NK) cytotoxicity was much greater with Mu-rIFN(β) than Mu-rIFN(γ), whereas Mu-rIFN(γ) enhanced the cytotoxicity of peritoneal macrophages more strongly than Mu-rIFN(β). Injection of Mu-rIFN(γ) i.p. 1 day before tumor challenge also inhibited the formation of pulmonary metastasis of B16-F10 melanoma. However, pretreatment of mice with carrageenan significantly suppressed the inhibitory effect of Mu-rIFN(γ). From these results, it is suggested that the inhibitory effect of Mu-rIFN(γ) on the tumor growth and metastases of B16-F10 melanoma is mediated partly by direct antitumor effect and partly by the activation of macrophages, and that the augmentation of NK activity contributes mainly to the antitumor effect of Mu-rIFN(β).

Clinical Implication of the Antidiuretic Hormone (ADH) Receptor Antagonist Mozavaptan Hydrochloride in Patients with Ectopic ADH Syndrome

Ectopic antidiuretic hormone syndrome is a medical emergency characterized by dilutional hyponatremia. Clinical effectiveness of the vasopressin V2 receptor antagonist mozavaptan was evaluated in 16 patients. In short-term (7-day) treatment with the drug, serum sodium concentration (mean ± standard deviation) significantly (P = 0.002) increased from 122.8 ± 6.7 to 133.3 ± 8.3 mEq/l, and symptoms due to hyponatremia were improved. On the basis of these results, mozavaptan (Physuline(®)) was approved as an orphan drug for the treatment of the syndrome in 2006 in Japan. During the 43 months following its launch, 100 patients have been treated with the drug; overall clinical effects of the drug were found similar to those of this clinical trial. Clinically, mozavaptan may allow hyponatremic patients to be treated by aggressive cancer chemotherapy with platinum-containing drugs. Moreover, the drug may free patients from strict fluid-intake restrictions and thereby improve their quality of life.

Three Schedules of Recombinant Human Interleukin‐2 in the Treatment of Malignancy: Side Effects and Immunologic Effects in Relation to Serum Level

Recombinant human interleukin‐2 (rIL‐2) was administered to 34 patients with advanced malignancy. Three schedules of rIL‐2 administration employed were as follows: (A) 2‐hr iv infusion of 6.7 × 10*5 U/m*2/day (A1, 6 cases) or 2.2 × 10*6 U/m*2/day (A2, 8 cases) for five consecutive days; (B) 24‐hr continuous iv infusion of 3.3 × 10*5 U/m*2/day (B1, 3 cases), 6.7 × 10*5 U/m*2/day (B2, 7 cases) or 1.1 × 10*6 U/m*2/day (B3, 5 cases) for 28 consecutive days; and (C) 24‐hr continuous iv infusion of 6.7 × 10*5 U/m*2/day (C, 5 cases) for 5 consecutive days per week for four weeks. The common side effects were fever (79%), eosinophilia (61%), malaise (56%), erythema or rash (50%), chills (38%) and nausea or vomiting (35%), with the dose‐limiting toxicities being hypotension in group A, and renal dysfunction with fluid retention in groups B and C. In the case of 2‐hr iv infusion, rIL‐2 was rapidly cleared from the plasma, with a half life of about 30 min, while in the case of 24‐hr continuous infusion, more than 1 U/ml serum IL‐2 activity was maintained for 14 days in group B3. Natural killer (NK) and lymphokine‐activated killer (LAK) activities were augmented by rIL‐2 administration in patients of groups A, B3 and C. In eight patients of group B, NK and LAK activities transiently decreased after rIL‐2 administration, and recovered by day 3. The percentage of IL‐2 receptor and Leu HLA‐DR positive cells reached the peak level on day 7 in group B. In patients of group C, the percentage of Leu HLA‐DR positive cells as well as NK and LAK activities increased upon rIL‐2 administration and decreased during an intermission of two days. However, the percentage of rIL‐2 receptor positive cells increased during the intermission of rIL‐2. The most effective schedule of rIL‐2 administration was considered to be the schedule of group C on the basis of this study.

Cytogenetic effect of carboplatin on human lymphocytes

SummaryCarboplatin, a second generation cisplatin analogue, was tested for induction of sister chromatid exchange (SCE) as well as chromosomal aberrations in human lymphocytes in vitro and in vivo. A dose-dependent effect was observed for increased frequency of metaphases with SCE (r=0.984, P(0.001) as well as chromosomal aberrations (r=0.994, P(0.001), primarily chromatid gap or break, in vitro. SCE induction by carboplatin was less than that by cisplatin at the same concentration. When patients were treated with a single dose of carboplatin at a dose of 450 mg/m2, the frequency of SCE and chromatid type aberrations increased significantly. However, even when considering dose and peak plasma concentration in patients receiving carboplatin, it appears that the ability of carboplatin to induce SCE and chromosomal aberrations is weaker than that of cisplatin. SCE frequencies induced by carboplatin decreased with time going by, and in one patient who was tested 5 weeks after treatment, SCE frequency showed a decrease to the pretreatment level. It thus appears that carboplatin has an improved therapeutic index over the parent compound, cisplatin, because of its less mutagenic or carcinogenic hazard, in addition to the largely reduced incidence of untoward effects.

The colony inhibition of a new chemotherapeutic agent (KW2152) against human lung cancer cell lines

The human tumor colony assay was used to evaluate the effect of a new chemotherapeutic agent (KW2152) on colony inhibition of four non-small cell lung cancer cell lines and a mouse cell line. With continuous exposure experiments, KW2152 induced > 70% colony inhibition of PC-7 (human adenocarcinoma), PC-10 (human squamous cell) and PC-13 (human large cell) at a drug concentration of 10 mcg/ml. In one hour exposure experiments, KW2152 caused a significant reduction in colony formation (< 30% of control) only at the highest concentration tested (100 mcg/ml). KW2152 showed significant in vitro activity against human non-small cell lung cancer cell lines. Due to these promising results, it was suggested that KW2152 should be evaluated in clinical trials.

In vivo augmentation of the cytotoxicity of spleen lymphocytes against syngeneic B-16 melanoma cells and the suppression of the artificial metastases in C57BL/6 mice by subcutaneous multiple injections of high dose human recombinant interleukin-2 (rIL-2).

SummaryThe cytotoxicity of spleen lymphocytes against YAC-1 cells, against syngeneic B-16 and F-10 melanoma cells was augmented not only by incubation of spleen lymphocytes with human recombinant interleukin-2 (rIL-2) in vitro, but also by injectingC57BL/6 mice with high dose rIL-2 for more than 3 consecutive days. In animals injected s.c. with multiple high dose rIL-2, the numbers of tumor nodules in the lung were significantly decreased 21 days after i.v. tumor inoculation. In addition, in these groups of animals no liver metastases were observed although live metastases were detected in 6/11 control mice.

Lack of Correlation between Interferon Levels Induced by Polyribonucleotides and Their Antimetastatic Effect

The inhibitory effect of poly(A)poly(U) on the pulmonary metastasis of B16-F10 melanoma was examined in comparison with that of poly(I,C)-L,C and poly(I)poly(C). The correlation between interferon (IFN) level and antimetastatic effect was also investigated. Intraperitoneal injection of poly(A)poly(U) (50 mg/kg) into C57BL/6 mice 24 h before intravenous inoculation of B16-F10 melanoma (1 X 10(5] caused a significant decrease (p less than 0.01) in the number of pulmonary nodules 14 days after tumor challenge. But poly(I,C)-L,C (1 or 0.2 mg/kg) and poly(I)poly(C) (5 mg/kg or 1 mg/kg) did not. From the kinetic study of IFN levels induced by polyribonucleotides, poly(I,C)-L,C showed the most potent IFN-inducing activity, followed by poly(I)poly(C) and poly(A)poly(U), in this order. Plasma IFN reached a peak at 6 h and still continued to be detected at 24 h after intraperitoneal injection of the polyribonucleotides. Against B16-F10 melanoma, the cytotoxicity of spleen cells stimulated by poly(A)poly(U) (50 mg/kg) was significantly (p less than 0.05) higher than that of spleen cells stimulated by poly(I)poly(C) (5 mg/kg) both at 12 and 24 h after intraperitoneal injection of those agents. The above results that there is no correlation between the IFN levels induced by polyribonucleotides and their antimetastatic effect. More extensive study of poly(A)poly(U) might give more fruitful results, which will give valuable information for future clinical trials of this lowly toxic promising agent.

Phase I/II study of combination chemotherapy with cisplatin, carboplatin and etoposide in small cell lung cancer

A Phase I/II study of combination chemotherapy with cisplatin (CDDP), carboplatin (CBDCA) and etoposide (VP-16) (CPVP) was conducted in patients with small cell lung cancer. The dose level of etoposide was fixed at 100 mg/m2, while the doses of CDDP and CBDCA administered at each of the four steps were 50/200, 60/200, 60/250 and 70/250 mg/m2, respectively. Nine patients were allocated to each step dose group. Adverse effects were evaluated during the first two courses to establish the maximum tolerated dose (MTD). As a result, the step 3 doses turned out to be the MTD. The dose-limiting factor was hematotoxicity. Gastrointestinal toxicity was also present, but was tolerated. The overall response rate in patients with measurable or evaluable lesions was 91%. In 22 chemotherapy-naive patients, the median survival time was 16.6 months. These results suggest that the recommended dose is step 2, and that the CPVP regimen might be both more tolerable and more effective than the standard PVP regimen. Based on the above findings, CPVP therapy warrants further study in Phase II and III trials.