Phase II study of CPT-11, a new camptothecin derivative, in metastatic colorectal cancer. CPT-11 Gastrointestinal Cancer Study Group.

PURPOSE: A phase II study was conducted to evaluate the antitumor effect and toxicity of CPT-11 in patients with metastatic colorectal cancer. PATIENTS AND METHODS: From December 1989 to March 1991, 67 patients with metastatic colorectal cancer were enrolled in this study. Sixty-three patients were assessable for toxicity and response. Their median age was 57 years (range, 24 to 72). Forty-six patients (73%) had a good performance status of 0 or 1. Fifty-one patients (81%) had received prior chemotherapy. The major sites of metastasis were liver (63%) and lung (44%). CPT-11 was administered as a 100 mg/m2 weekly intravenous infusion, or as 150 mg/m2 every 2 weeks. The dose was reduced based on the grade of leukopenia and diarrhea, if necessary. RESULTS: A partial response was obtained in 17 of 63 assessable patients (27%; 95% confidence interval, 16% to 38%). The response rate in patients with prior radiotherapy or chemotherapy was 25% (13 of 52). Liver metastases showed a 15% (six of 40) response and lung metastases showed a 39% (11 of 28) response. The median duration of partial response was 127 days (range, 49 to 353) and the median overall duration of response was 208 days (range, 99 to 381). The major toxicities (> or = grade 3) were leukopenia (16%), diarrhea (13%), nausea and vomiting (13%), and alopecia (11%). Adverse effects were generally well tolerated and reversible. Treatment could be continued on an outpatient basis for patients without severe toxicity. Hemorrhagic cystitis was not encountered in this study. CONCLUSION: CPT-11 showed promising antitumor activity against metastatic colorectal cancer that was resistant to prior therapy. Further clinical trials of combination chemotherapy using CPT-11 are justified.

Potential of the histoculture drug-response assay to contribute to cancer patient survival.

The histoculture drug-response assay (HDRA) was recently evaluated in a retrospective clinical trial and was found to correlate to drug sensitivity, resistance, and patient survival. To further investigate the potential of HDRA to contribute to patient survival, 215 patients with gastric cancer from 45 medical centers were tested with the HDRA in a blinded study after resection of the primary lesion. One hundred sixty-eight patients received at least 20 mg/m2 of mitomycin C and a minimum of 30 g UFT, a mixture of tegafur and uracil at a molar ratio of 1:4, thereby making them eligible for the study. Of these cases 128 were evaluable by the HDRA. The evaluable patient tumors were tested by the HDRA with the [3H]thymidine incorporation end point measured by microautoradiography to be drug "sensitive" or "resistant." The in vitro conditions for distinguishing sensitivity and resistance that matched the response rates for historical controls for gastric carcinoma were 90% inhibition rate and 0.12 microgram/ml for mitomycin C and 70% inhibition rate and 1 microgram/ml for 5-fluorouracil, respectively. Most importantly in the blinded study, the overall and disease-free survival rates of the HDRA-sensitive group were found to be significantly higher than those of the HDRA-resistant group tested under the above conditions. The data further indicate the importance of three-dimensional tumor culture for obtaining accurate clinical information. The results demonstrate that the HDRA response correlates to patient survival, which suggests the potential of the HDRA to contribute to patient survival in gastric cancer when used prospectively.

In vivo radiosensitivity and recovery pattern of the hematopoietic precursor cells and stem cells in mouse bone marrow.

Survival curves were determined for colony-forming hematopoietic stem cells (CFU-Mix and CFU-S10) as well as precursor cells (CFU-E, CFU-C, CFU-F, and BFU-E) in bone marrow of the mouse at various times up to 4 weeks after whole-body irradiation (1.5 or 3.0 Gy) in order to elucidate in vivo radiosensitivity and recovery patterns. These measurements represented the first attempts to examine CFU-Mix simultaneously with the other cell populations. CFU-E (D0 = 53 rad) and BFU-E (D0 = 68 rad) were the most radiosensitive. CFU-S10 (D0 = 81 rad) had intermediate radiosensitivity. CFU-Mix (D0 = 144 rad) and CFU-C (D0 = 157 rad) were relatively radioresistant. CFU-F (D0 = 257 rad) was the most radioresistant. The precursor and stem cells could be classified into three groups based on the recovery pattern. The first group, consisting of CFU-Mix, BFU-E, and CFU-S10, showed very slow recovery and did not reach normal levels even after day 28. CFU-E, the second group, showed the most severe depletion immediately after irradiation, and recovered most quickly with an overshoot at day 5. CFU-C and CFU-F cells, forming the third group, decreased more gradually and slightly, and recovered to the normal level after a transient rise by day 10-14.

Effects of recombinant granulocyte colony-stimulating factor (rG-CSF) and recombinant granulocyte-macrophage colony-stimulating factor (rGM-CSF) on acute radiation hematopoietic injury in mice.

We have attempted to evaluate in vivo effects of granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF) on acute radiation hematopoietic injury in mice. BDF1 mice, irradiated with 7.5-Gy x-rays, were injected i.p. twice daily for 10 days with 10(5) U recombinant human G-CSF, 3.75 x 10(5) U recombinant murine GM-CSF, or a combination of both. G-CSF significantly enhanced the recovery of not only peripheral leukocytes but also platelets and hematocrit on days 14 and 21 after irradiation. GM-CSF significantly enhanced the recovery of platelets on day 14 and peripheral leukocytes on day 21. G-CSF markedly enhanced the recovery of spleen colony-forming units (CFU-S), colony-forming units in culture (CFU-C), erythroid burst-forming units (BFU-E), and megakaryocyte colony-forming units (CFU-Meg) both in bone marrow and in the spleen. GM-CSF significantly enhanced the recovery of CFU-Meg in bone marrow on day 14. We found synergistic effects between G-CSF and GM-CSF on CFU-S, CFU-C, and CFU-Meg in the spleen on day 14, although we found antagonistic effects between G-CSF and GM-CSF on CFU-S and CFU-C in bone marrow on day 7, and on platelet counts on day 7. These results indicate that the administration of recombinant G-CSF and GM-CSF may be useful in accelerating hematopoietic recovery in patients with acute radiation hematopoietic injuries.

Induction of mammary carcinomas by the direct application of crystalline N-methyl-N-nitrosourea onto rat mammary gland.

The effectiveness of the direct application of crystalline N-methyl-N-nitrosourea (MNU) onto the mammary gland was compared with the systemic intraperitoneal (i.p.) administration method for the induction of mammary carcinomas in female Sprague-Dawley (S-D) rats. The effectiveness was also tested in genetically resistant female Copenhagen (Cop) rats. The 10 mg crystalline MNU was dusted directly onto the right-inguinal mammary gland, or 50 mg/kg body weight MNU solution was given i.p. at 50 days of age. Animals were palpated for tumor detection twice weekly and killed when the tumor reached 1-2 cm in diameter or were necropsied 30 weeks after carcinogen treatment. In S-D rats, all of the 78 tumors produced by dusting were adenocarcinomas. By contrast, 40 tumors produced i.p. were adenocarcinomas, 1 was fibroadenoma, and 5 were lactating adenomas. The cumulative incidence of mammary carcinoma was high in the dusting and the i.p. groups (12/12; 100% and 11/13; 84%, respectively). However, the dusting groups showed a high number of carcinoma per rats (6.5 vs. 3.6; P < 0.01) and short cancer latency (13.8 weeks v.s. 28.1 weeks; P < 0.001) than the i.p. groups. In Cop rats, although low (4/11; 36%), adenocarcinomas were developed by the dusting method. In both strains, adenocarcinomas displayed various degrees of differentiation but no evidence was found for metastasis. For MNU-administration, the direct dusting technique is an effective method and offers added advantages of ease for the induction of mammary carcinomas in rats.

Clinical experiences with aclacinomycin-A.

Aclacinomycin is a new anthracycline analog of adriamycin and daunomycin. Aclacinomycin contains three sugars. The drug has been studied in 22 cases in a phase 1 type of trial on a schedule 20 mg i.v. every other day up to a total of 300 mg. Toxicity has consisted of myelosuppression, nausea and vomiting, and transient hepatic disturbances. Evidence of clinical activity was observed in several cases including a case of breast cancer and gastric cancer. Although no full patial remissions were recorded, further study is continuing.

N-methyl-N-nitrosourea-induced photoreceptor apoptosis in the mouse retina.

Retinal degeneration induced by a single intraperitoneal injection of N-methyl-N-nitrosourea (MNU) in male and female albino (GRS/A and DDD/1) and colored (C57BL) mice at 7 weeks of age was examined morphologically 1, 3, 7, 14 and 21 days after the treatment. A dose of 60 mg/kg body weight evoked progressive retinal degeneration in all mice. All albino and colored mice had a comparable progression of photoreceptor cell degeneration by an apoptotic mechanism, as confirmed by morphological and TUNEL methods. Apoptosis had already taken place 1 day after the treatment and was completed by Day 7. This process resulted in a thin remnant of retina with complete loss of photoreceptor cells-21 days after the treatment. During the course of apoptosis, the pigment epithelial cells were maintained in a continuous layer in all strains of mice. In colored mice, several layers of the swollen pigment-enriched cells were seen between the inner nuclear layer and the pigment epithelial layer 14 and 21 days after the treatment. In summary, the destruction of photoreceptor cells by the apoptotic process was the mechanism by which retinal degeneration was induced by MNU.

Improved lipid visualization with a modified osmium tetroxide method using ultrasonic treatment and intensification with imidazole or triazole.

Formalin fixed autopsy tissue containing lipids were cut into 1-5 mm thick blocks, washed well, then postfixed in 2% OsO4 in 0.03 M veronal acetate buffer for 30, 60, 90, 120, or 180 min with or without ultrasonic treatment. Tissues exposed to ultrasound for 90 min showed superior penetration of OsO4 and well preserved histological architecture. Tissues also were immersed for 1 hr in veronal acetate buffer (pH 7.4) containing 0.5% imidazole or triazole and compared with untreated controls. Paraffin sections, 4 microns thick, were examined under a light microscope with an image analyzer. Both intensity and percentage area of osmium blackening were significantly higher in samples immersed in imidazole or triazole than in untreated controls. No difference was observed between imidazole- and triazole-immersed samples. The OsO4 method, modified by ultrasound treatment and imidazole- or triazole-immersion, can be applied to routine formalin fixed autopsy materials for improved lipid visualization.

A mixture of paraphenylenediamine and imidazole: its effect on the extraction of lipid droplets during electron microscopy staining.

To prevent extraction of lipids during a double staining procedure for electron microscopy, the tissue slices, double fixed with glutaraldehyde and osmium tetroxide to preserve microvesicular lipid droplets in the cytoplasm, were immersed for 2 hr in veronal buffer (pH 9.0) containing 0.5% p-phenylenediamine and 0.5% imidazole immediately after postfixation. The stained sections of the immersed tissue slice showed blackened, well circumscribed lipid droplets similar to those in corresponding unstained sections. Moreover, highly contrasting features of the cellular architecture could be visualized with the double stained, as well as routinely prepared sections.

[Experience in combination therapy with amikacin and cephapirin for infections complicated with acute leukemia during induction chemotherapy].

We treated infections accompanied with induction chemotherapy in 9 patients with acute leukemia by the combination of amikacin (AMK) and cephapirin (CEPR). The result was that 1 case was markedly effective, 2 cases were effective, 3 cases were marginally effective, 2 cases showed no effect and 1 case who underwent prophylactic medication had no infection. We recognized no adverse effects by AMK or CEPR. We concluded that the combination of AMK and CEPR was useful as first choice to the treatment of infections during induction chemotherapy of acute leukemia.

[Hepatic failure and renal failure in antineoplastic chemotherapy, and its treatment].

Various degrees of hepatic failure and renal abnormality may occur as complications of anti-neoplastic chemotherapy. The etiologies of alterations in liver function and the clinical pictures of chemotherapeutic agents as potential hepatotoxins, and of drugs with hepatic metabolism, and their combination uses, are discussed. As strategies are available for prevention and amelioration of these problems, management by periodic reevaluation of liver function is most important. In renal failure, myeloma kidney as tumor-associated nephropathy, hyperuricemic nephropathy and treatment-related nephrotoxicity are discussed with regard to their etiologies and clinical pictures. Aggressive management with intravenous hydration can ameliorate these complications of therapy, and careful monitoring of renal function and serum electrolytes are essential during administration of these agents.

[Some problems of the criteria for response evaluation of cancer chemotherapy of the digestive organs].

The criteria for response evaluation of cancer chemotherapy of digestive organs were discussed on the clinical application of stomach and esophagus cancer which the criteria are almost established. The responses of primary site are evaluated on the changes of tumor size by imaging diagnosis, and the uniformity and objectivity of response representation due to the sort of lesion cause the problems, so for studies are carrying out in many cases. Furthermore, response rate, survival time and quality of life were discussed in relation to clinical studies how to manage it at present and the problems in future referred. The criteria for response evaluation is a rule and interpreted different senses due to the objects of clinical studies. According to accumulate the clinical studies with exact significances and objects, various problems will be solved.

[Adverse reactions to carcinostatics and countermeasures].

As adverse reactions to the combination treatment by the digestive system, we observed the occurrence of nausea and vomiting in 15% of the cases who received FTP treatment consisting of 5-FU, toyomicin and prednisone, 25% of the cases who received MFU treatment consisting of MMC, 5-FU and ACNU, and in 64% of the cases who received PPQ treatment consisting of CDDP, Carboquone (CQ) and prednisone. The antiemetics usually used are metoclopramide and droperidol, and we preadminister valproate preparation when persistent and delayed emesis is predicted. Several randomized trials have been made, and good efficacies with drugs such as metoclopramide, domperidone and steroid have been reported. Efficacy was good with acute emesis, but nonexistent with delayed emesis. As to the liver injury, in our combination treatment, only one case showed elevation of GPT by more than 500 units in the cases treated with MFU, while, increase in liver enzymes in the blood was observed in 10-20% of the cases. Similarly, there were not so many cases of liver injury during PPQ treatment. Thus, liver injury due to carcinostatic would be less frequent. Moreover, autopsy revealed hepatocellular-type of liver injury, cholestatic type liver injury and fatty metamorphosis at reasonable incidence. There were no typical cases of veno-occlusive disease which are noticed recently. The most important point for prevention and countermeasures against liver injury is to be careful not to use the previously mentioned drugs exhibiting toxicity in the liver if hepatic disease exists.

[A tentative of guideline for phase III study and its problems in clinical aspect].

A draft of guideline for phase III study of anticancer drugs was presented, and its objective problems in practical aspect was discussed. The anticipated of phase III study is to evaluate the clinical usefulness of anticancer drug in terms of effectiveness and toxicity. And the comparative study of new drugs with standard therapy is most important. The comparative study includes two trials: randomized controlled trial and the second non-randomized controlled trial. Considering the precision of study, the randomized controlled trial is most rational, but it includes some controversies in practical use and ethical aspect. On the other hand, non-randomized controlled trial includes some problems on comparability in relation to prognostic factors.

[Electrolyte metabolism and emergency].

In outlining the pathology of various electrolyte metabolism abnormalities in cancer patients we considered the main clinical points between pathologies and emergency treatment. In regard to sodium (Na+) metabolism, one pathologic state that requires our attention is hypernatremia. Hypernatremia is accompanied with dehydration and is due to water loss, vomiting, diarrhea and renal insufficiency. One of the major causes of this condition is lack of the antidiuretic hormone due to intracranial metastasis of the tumor. When hypernatremia becomes severe, it is accompanied with circulatory failure, muscular asthenia, disorientation, convulsions, coma and other cerebral symptoms. Treatment consists of replenishing the water content by infusion of electrolyte solutions which should be carefully conducted after complete diagnose of the severity of the patient's pathological condition. Hyponatremia, like sick cell syndrome, is observed relatively frequently in cancer patients. When the serum Na level falls markedly, it induces cerebral edema and causes disorders of consciousness. The major treatment consists of providing both water and sodium supplements. Hyperkalemia is observed at the time of renal insufficiency, tissue lesions, vomiting, and diarrhea. When serum potassium level rises, it causes bradycardia, ventricular fibrillation, or cardiac arrest. It is important to diagnostically apprehend the severity of this condition using EKG and determining the serum K1+ level. For emergency treatment injection of calcium gluconate is very effective. Hypokalemia is often manifested by the loss of intestinal fluids due to diarrhea or during administration of diuretic agents. Clinical symptoms include neural paralysis but emergencies occur relatively infrequently. K C1 injections are used in treating this condition. Hypercalcemia is manifested in cancer patients during hyperparathyroidism. Its clinical symptoms include lassitude, tachycardia, nausea, vomiting, and renal dys-function, leading to neural symptoms in severe cases. The main treatment consists of injection of physiological saline solution and administration of calcitonin, mithramycin. Hypocalemia is manifested during renal insufficiency, lack of vitamin D, and hypothyroidism. In classic cases it causes tetanic spasms. Injection of calcium is an effective treatment but since during tetanic spasms alcalosis may easily occur, treatment should only be provided after obtaining a complete understanding of the patient's condition. The pathological conditions described above can not be said to specific to cancer but it should be kept in mind that one of their main causative factors is the involvement of mechanism which produces ectopic hormones from cancerous tissues.

[Phase II study of (2" R)-4'-O-tetrahydropyranyladriamycin (THP) in patients with advanced or recurrent gastric cancer. Clinical study group of THP for gastric cancer in Japan].

A multi-institutional collaborative phase II study of (2"R)-4-O-tetrahydropyranyladriamycin (THP) was performed by intravenous administration to patients with advanced or recurrent gastric cancer. The administration schedules were (1) 40-60 mg/body every 3 or 4 weeks and (2) 20-40 mg/body once a week. Of 58 registered patients, 49 cases were eligible and 37 cases were evaluable for response. The therapeutic results were 1 CR, 4 PR, 14 NC and 18 PD. The response rate of the evaluable cases was 13.5%. The side effects were mainly bone marrow suppression and digestive symptoms. In particular, the frequency of leukopenia was a high 75.5%, while there was a decrease in hemoglobin in 38.8% and anorexia in 30.6%. The frequency and severity of alopecia, which is a known problem with anthracyclines, were slight, and no abnormal electrocardiograms were observed.

[Phase I clinical study of zinostatin stimalamer (YM 881) by intravenous injection].

A phase I clinical study by intravenous injection of zinostatin stimalamer (YM 881), a protein anti-cancer drug, was conducted in 50 patients with malignant tumors. The initial dose was 0.5 mg/m2 (n) in the single dose test, and 0.2 mg/m2/day in the repeated dose test for 5 successive days. Doses were increased up to 12n according to the modified Fibonacci's method in both the single and repeated dose tests. The dose limiting factor was thrombopenia in both the single and repeated dose tests. The maximum tolerated dose was 6.0 mg/m2 (12n) in the single dose test, and the subtoxic dose was 2.4 mg/m2/day in the five day repeated dose study. These results indicate that dose of 1.0 to 1.4 mg/m2/day (5 n to 7 n) are appropriate for the phase II repeated dose study.

[Early phase II study of YM 881 (zinostatin stimalamer) by intravenous injection. Research group for intravenous YM 881].

An early phase II multicentered study of YM 881 (zinostatin stimalamer) was conducted in 36 patients to investigate response and the safety of the drug in malignant tumors. The response could be evaluated in 18 patients, one with brain tumor, 2 with lung cancer, one with breast cancer, one with liver cancer, one with pancreatic cancer, 6 with gastric cancer, and 6 with colon cancer. PR was found in the patient with brain tumor. Major subjective unwanted effects were gastrointestinal symptoms. Objective evidence of hematological changes (thrombocytopenia, decreased hematocrit, and lymphocytopenia) was also obtained.

[Phase II study of YM881 (zinostatin stimalamer) suspension injected into the hepatic artery. Research Group for Intra-arterial Injection Therapy with YM881].

A phase II study of YM 881 (zinostatin stimalamer) to determine the response and safety was conducted in patients with hepatocellular carcinoma by injecting a suspension of the drug into the hepatic artery. Repeated doses of 4 to 6 mg of the drug were given every 4 weeks so that the tumor tissues were filled with the suspension. Of the 195 registered patients, 15 were ineligible for the study, 8 dropped out, and data were missing for 5. A total of 167 patients completed the study. Response was assessed in the 167 patients who completed the study. CR was found in one, PR in 59, MR in 25, NC in 67, and PD in 15, with a response rate of 35.9. The safety of the drug was assessed in 177, excluding ineligible patients and 3 who dropped out because of the concurrent use of other drugs. Adverse reactions were found in 93.2% of the patients, and abnormal values in clinical laboratory tests in 60.5%. Major unwanted symptoms included fever, nausea, vomiting, and anorexia. Major abnormal changes in laboratory tests were elevated total bilirubin and LDH and abnormal hepatic function. About half the patients had malaise and pain related to the intra-arterial infusion therapy. The one year survival rate was 56.9%, and the duration of survival of 50% of the patients was 407 days.

[Phase I study of YM881 (zinostatin stimalamer) suspension by hepatic arterial infusion. Research Group for Intra-arterial Infusion Therapy with YM881].

A phase I study of YM-881 (zinostatin stimalamer), neocarzinostatin combined with butylesterified styrene maleate, suspended in iodized poppy oil ethyl ester, was conducted in patients with hepatocellular carcinoma by giving single intra-arterial infusions via catheters inserted by Seldinger's method. Four dose levels, 2, 4, 6, and 8 mg, were tested. Major adverse reactions were fever, anorexia, nausea, vomiting, and abnormal hepatic function. Both the incidence and severity of adverse reactions tended to increase with the 8 mg dose. Tumor regression of 50% or more occurred in one receiving 2 mg and one receiving 4 mg. The results of the study suggest that doses of 6 mg or less may be appropriate for the phase II studies.