Phase II study of neoadjuvant chemotherapy and extended surgery for locally advanced gastric cancer.

BACKGROUND: Locally advanced gastric cancer with extensive lymph node metastasis is usually considered unresectable and so treated by chemotherapy. This trial explored the safety and efficacy of preoperative chemotherapy followed by extended surgery in the management of locally advanced gastric adenocarcinoma. METHODS: Patients with gastric cancer with extensive lymph node metastasis received two or three 28-day cycles of induction chemotherapy with irinotecan (70 mg/m(2) on days 1 and 15) and cisplatin (80 mg/m(2) on day 1), and then underwent gastrectomy with curative intent with D2 plus para-aortic lymphadenectomy. Primary endpoints were 3-year overall survival and incidence of treatment-related death. RESULTS: The study was terminated because of three treatment-related deaths when 55 patients had been enrolled (mortality rate above 5 per cent). Two deaths were due to myelosuppression and one to postoperative complications. Clinical response and R0 resection rates were 55 and 65 per cent respectively. The pathological response rate was 15 per cent. Median overall survival was 14.6 months and the 3-year survival rate 27 per cent. CONCLUSION: This multimodal treatment of locally advanced gastric cancer provides reasonable 3-year survival compared with historical data, but at a considerable cost in terms of morbidity and mortality.

[Results of combination therapy of UFT-E with low-dose CDDP for patients with advanced recurrent breast cancer].

CDDP, as a modulator for 5-FU, has already been described as a very effective treatment for gastrointestinal tract cancer. We administered a dose of 400 mg of UFT-E orally every day, and 10 mg of CDDP by drip infusion twice weekly, for more than 10 weeks to 12 outpatients with metastatic local, pulmonary, hepatic, osteal or multiple-organ cancer which showed a poor response to the pretreatment, and assessed its efficacy and drug toxicity. In terms of the clinical efficacy of this therapy, CR was noted in one patient and PR in 2 patients with a response rate of 25%. The incidence of drug toxicity was low. Complications included temporal transient nausea and anorexia in two patients and leukopenia grade 2 as bone marrow suppression in 3 patients. From the standpoint of QOL, as well as in terms of both antitumor effect and drug toxicity, the therapy mentioned above was believed to be effective for outpatients with advanced recurrent breast cancer.

[Effect of leucovorin and 5-FU for advanced colorectal cancer patients].

In 17 cases of advanced colorectal carcinoma with accessible metastatic lesions, a low dose of leucovorin (LV, 30 mg/body) + 5-fluorouracil (5-FU 500 - 750 mg/body) was administered intravenously as a bolus injection, or by injection into the hepatic artery from a reservoir. Two of the 12 patients (16.7%) who received intravenous injection, and one of the five cases who received intra-hepatic artery injection showed partial response (PR). The side effect of this treatment was mild, and the performance status of the patients was excellent. This article deals with 3 PR cases. Case 1 had a bipulmonary multiple metastasis. When LV + 5-FU was administered intravenously, a reduction rate of 87% was obtained, and the patient survived for 27 more months. Case 2 had paraaortic lymph node metastasis. When LV + 5-FU was administered intravenously, a reduction rate of 59% was obtained, but the patient died after 9 months. Case 3 had a multiple liver metastasis. LV + 5-FU was administered intravenously in the liver, and a reduction rate of 69% was achieved. The patient survived for 30 months from the administration. LV + 5-FU is an effective treatment for advanced colorectal cancer. In the future, more research should be conducted to study the amount and method of administration, and combined treatment, to increase the response rate and to extend the period of good health.

[Clinical study on stage PT1 and grade 3 transitional cell carcinoma of the urinary bladder].

Thirty-three patients who had transitional cell carcinoma of the bladder with stage PT1 and grade 3 components were treated between January 1980 and December 1992. Clinical study was done for these 33 patients on treatment modalities and it's problem, intravesical recurrence, disease progression and prognosis. Twenty-five of 33 patients underwent bladder-sparing surgeries and total cystectomy was performed for another 8 patients as initial treatment. Intravesical recurrence was observed in 18 (72%) of 25 patients who underwent initial bladder-sparing surgeries. Recurrence-free rate was 44% for 1 year and mean period to recurrence from initial therapy was 13.1 months. Although some adjuvant therapy after initial treatment was performed for 20 patients, it's efficacy in preventing intravesical recurrence could not be confirmed. Disease progression was recognized in 10 (40%) of 25 patients initially treated by bladder-sparing surgeries after median latent period of 33.7 months, whereas only one (12.5%) of another 8 patients who underwent total cystectomy showed progression, and 5-year progression-free rate after initial bladder-sparing surgeries was 55.6%. Three and five-year actural survival rate in all cases were 81.5% and 65.1%, respectively. According to initial treatment, 5-year survival rate was 62.2% for the patients treated by bladder-sparing surgeries, whereas it was 83.3% for the cases who underwent total cystectomy. However statistical significant difference was not recognized. In view of disease progression after initial bladder-sparing surgeries, patients with progression yealed a 45.7% 5-year survival rate compared to 81.5% for the patients without progression, and significant difference was demonstrated between them.(ABSTRACT TRUNCATED AT 250 WORDS)

[A case of postoperative pulmonary metastasis of colon cancer which responded to treatment with leucovorin and 5-FU].

A 72-year-old man underwent a radical operation for sigmoid colon cancer (well-differentiated adenocarcinoma, stage III) in 1989. Chest X-ray examination performed in September 1992 showed multiple nodular shadows in the lungs. A diagnosis of pulmonary metastasis was made from abnormally increased CEA and CA 19-9 and findings by chest tomography and CT scanning. There was no evidence of metastasis or recurrence in the liver, bone, brain or large intestine. He received three courses of bolus injections of leucovorin (30 mg/body) and 5-FU (500 mg/body), each over five consecutive days with a two-week rest period, and subsequently weekly at the same doses. CEA and CA 19-9 levels started to decrease after completion of the second course of consecutive treatment. In week 18 of chemotherapy, CEA and CA 19-9 levels dropped to 5.6 ng/ml and 32 U/ml from 66 ng/ml and 130 U/ml, respectively. Chest tomography and chest CT showed the disappearance or reduction in size of the nodules, with a reduction rate of 87.1%. Twenty-two weeks later, at this writing, there was no evidence of disease progression, and the patient was thus judged to be PR. He continues to receive chemotherapy at our outpatient clinic.

[A retroperitoneal leiomyosarcoma--a case of non-concurrent double cancers with kidney cancer].

A retroperitoneal leiomyosarcoma in a 50-year-old man is reported. A laparotomy was performed on Dec. 17, 1987 and the tumor, weighing 120 g, was completely excised. The patient was followed up and has stayed healthy (1 year after operation). Although CT ultrasonography and arteriography are helpful in the diagnosis of retroperitoneal tumors, it is felt that a histological examination is indispensable for a qualitative assessment of the lesion. Surgical excision constitutes the fundamental treatment for a retroperitoneal leiomyosarcoma. However, the prognosis is usually poor and depends on successful radical surgery. This case involved non-concurrent double cancers with a retroperitoneal leiomyosarcoma and a kidney cancer.

[Case report of a second resection of rectal leiomyosarcoma due to recurrence after 10 years].

A leiomyosarcoma of the rectum is a rare disease, and cases of a recurrence are even more rare. Reported is the case of a patient who, in 1987, underwent a per sacral resection of a rectal tumor which was diagnosed as leiomyosarcoma. In 1987, after symptoms that showed that the patient's feces had become narrower, a recurrence of this tumor was diagnosed, so that the patient again underwent an abdominoperineal rectomy. The postoperative course has been good. Details of this disease still remain unclear. In Japan, there have been only 10 such cases of a recurrence reported. Of these, a liver metastasis and a localized recurrence are the most common. Long term follow-ups are considered necessary.

[A case of leiomyosarcoma of the small intestine with perforative peritonitis].

On April 15th, 1986, the patient, a 58-year-old man, felt ill because of a stomachache. On April 15, he was referred to our hospital and admitted after having been diagnosed as having pan peritonitis. During surgery, an extraintestinal growth, a small fist-size tumor, was detected in the jejunum. The tumor was partly perforated, and a partial resection of the small intestine was carried out. A histopathological examination led to the diagnosis of a leiomyosarcoma of the small intestine. On June 12, 1987, the patient again returned to our hospital, complaining of a stomachache. A reoperation was performed for perforative peritonitis due to its recurrence but only palliative treatment could be provided.

[A case of an exogastric developing-type carcinoma of the stomach and a review of thirty nine cases reported in Japan].

One personally handled case of an exogastric developing-type carcinoma of the stomach and 39 other cases reported in Japan are discussed in this study. Twenty-seven cases mainly involved an abdominal tumor. As to the developing region, it was frequently in the greater curvature of the antrum. By tissue type, many undifferentiated medullary cancers were noted. With regard to treatment, many researchers recommend the excision of the other complicated organs. Survival for more than postoperative 1 year were as few as 4 cases, including the case handled.

[Clinical evaluation of tumor markers in breast cancer patients].

During the past 4 years, the performances of various tumor markers such as CA15-3, CEA, ferritin, beta 2-microglobulin and TPA have been evaluated in 78 cases of mammary cancer. The results were categorised according to differences in stages, difference in values from patients with recurrent tumors, the incidence of abnormal values and differences in values before and after surgery. When the incidence of values higher than the cutoff value was determined for each of stage I, II and III + IV, the rates for CEA were 14.3%, 4.9% and 27.8%, respectively, whereas those for TPA were 25.0%, 22.2% and 26.7%, respectively. In addition, for CA15-3, the incidences were 0% in stage I, 5.0% in stage II and 57.1% for combined stages III + IV. The average values for patients with recurrent tumors were 3.2 ng/ml CEA, 194.5 ng/ml ferritin, 316.2 U/l TPA and 81.3 U/ml CA15-3. The rates of abnormal values were 40.0% for CEA, 40.0% for ferritin, 85.7% for TPA and 63.6% for CA15-3. Differences in the values after surgical removal of the tumor were observed with these tumor markers: the CEA value was reduced from 1.6 +/- 1.4 to 1.1 +/- 0.5 (p less than 0.01) and the CA15-3 value from 12.2 +/- 8.4 to 9.3 +/- 4.1 (p less than 0.05), respectively, whereas that for ferritin was conversely increased from 48.9 +/- 48.0 to 74.0 +/- 70.0 (p less than 0.01). However, the values for TPA, despite showing a tendency to decrease, did not show any statistically significant alteration. The fluctuations of these marker levels in patients with recurrent tumors reflects the progress of the disease, with a sudden elevation in values indicating imminent death. The diagnostic significance of these markers is not high, but they are considered to be useful in detecting the progress or condition of a recurrent tumor.

[Observation on natural killer cell activity in gastric cancer patients and effect of nonspecific immunopotentiator administration on its postoperative reduction].

Natural killer cell (NK) activity, together with various nonspecific immunologic parameters, was measured preoperatively, and its changes induced by operative stress were examined in gastric cancer patients. Effect of administration of a nonspecific immunopotentiator, OK-432, was evaluated by postoperative changes in NK activity. Peripheral blood NK activity was measured by 51Cr-release assay against K-562 target cells. It was found that NK activity in the gastric cancer patients was significantly lower than that in healthy subjects. The reduction was specially marked in the cases of cancer at stages I and IV. NK activity in the cases with hepatic or peritoneal metastasis was significantly lower than that in the cases without such metastasis. NK activity in the cases of noncurative gastric resection or non-resection was significantly lower than that in the cases of curative gastric resection. NK activity in the cases of stage IV and "por" in histology was significantly lower than that in the cases of stage IV and "tub1" in histology. In the cases at stages I + II, there was a positive correlation between NK activity and IgG FcR(+) T cell ratio. There was a negative correlation between NK activity and alpha 2-globulin ratio and the correlation was especially significant in the cases at stages III + IV. In the cases at stages III + IV, receiving administration of OK-432 only postoperatively, NK activity was significantly reduced or tended to be reduced at 1 through 4 week(s) postoperatively, while such a reduction was not seen in the cases receiving administration of OK-432 pre- and postoperatively. This phenomenon was more marked in the cases showing a serum albumin level lower than 3.5 g/dl or in the cases undergoing operations longer than 4 hours in duration.

[Relations of tumor-specific cytotoxicity to nonspecific immunological parameters and to clinical course in various surgical cancer patients].

Human malignant cells, obtained from surgical specimens or pleuro-peritoneal exudate in 105 cases, were cultivated. Tumor-specific immunity was estimated by cytotoxicity assay using mixed autologous lymphocyte-tumor cell culture in 27 cases (40 times in all). Relations of the observed specific immunity to various nonspecific immunological parameters and to clinical responses to immunotherapy were examined. Positive reaction was observed in 14 examinations. Eight of 25 digestive tract cancers and 6 of 15 other cancers were positive. Cytotoxic activity was significantly higher in the group of favorable clinical response than in the group of progressive disease. In the group of positive cytotoxicity, incidence of clinical response was significantly higher than in the group of negative cytotoxicity. A significant positive correlation was found between cytotoxicity and T cell ratio. Incidence of positive cytotoxicity tended to be higher in the cases of single OK-432 administration (6/11). Incidence of clinical response was higher in the cases of combined OK-432 and PSK administration group (4/14). In the positive cytotoxicity group, 3 examinations showed progressive disease and 5 showed no change. It has been suggested that a higher incidence of favorable clinical response is to be expected in case of positive cytotoxicity, if some therapy will be combined with the conventional immunotherapy.

[Clinical studies on preoperative nonspecific immunological parameters and radical operation in stomach cancer].

Ratio of IgG Fc receptor positive T (Fc R(+) T) cell, PHA-induced blastogenesis and serum alpha 2-globulin ratio were examined in 90 preoperative cases with gastric cancer and were analyzed according to various stages of cancer and compared with normal controls. Moreover, on the basis of correlations among these parameters, operative radicality and prognosis were discussed. Fc R(+) T cell ratio was significantly elevated. PHA- blastogenesis was significantly reduced. Alpha 2-globulin ratio tended to increase as the stage progressed. A significant negative correlation was found between Fc R(+) T cell ratio and PHA- blastogenesis. In a scattergram indicating this correlation, the group of noncurative resection or exploratory laparotomy was divided into two areas, B1 and B2. The group of curative resection (A1) was located between B1 and B2, and the normal control group was located in the area common to B1 and A1, Cases succumbing to cancer within one year postoperatively were found to accumulate either in the area B2 or in the area B1 minus the area common with A1. No significant correlation was found between Fc R(+) T cell ratio and alpha 2-globulin ratio. However in a scatter gram, the almost same relationship between these three groups was noted. Thus it has suggested that postoperative prognosis (at least for two years) is good in cases which an immunological harmony among these parameters is maintained preoperatively.

[Experimental study on immunological effect of splenectomy on tumor-bearers].

In view of popularity of splenectomy in combination with gastrectomy for gastric cancer, immunological effect of splenectomy was studied experimentally, using SD rats and 3-methylcholanthrene-induced mammary cancer, MRMT -1. Splenectomy was performed on day -14, 2, 7, 14 or 21 of sc inoculation of 200 mg (about 4 X 10(6) cells) of MRMT -1 at the back of 4-week-old female rats. Tumor growth and immunocompetence of peripheral lymphocytes, spleen cells and thymus cells were examined. Tumor growth on day 35 tended to be inhibited in rats splenectomized on day -14, 2, or 14, while it tended to be promoted in rats splenectomized on day 7. PHA-induced blastogenesis and NK activity of spleen cells were reduced on day 2, rose on day 7 and gradually decreased on days 14 and 21. Winn's neutralization assay revealed that spleen cells on days 2, 14 and 21 of tumor inoculation had suppressor activities. In conclusion, spleen cells of tumor-bearing rats showed a reduced immunocompetence on day 2 (the early tumor-bearing stage) and on day 14 and later (the late tumor-bearing stage), while they showed a raised immunocompetence on day 7 (the middle tumor-bearing period).

Experimental study on merits and demerits of splenectomy in tumor bearers.

Immunologic merits and demerits of splenectomy were studied using a rat's experimental tumor. When splenectomy was done on day - 14, 2, or 14 of tumor inoculation, subsequent tumor growth was inhibited, but when it was done on day 7, tumor enhancement was observed. On day 2, cpm values of phytohemagglutinin (PHA)-induced blastogenesis of splenocytes was lower than in normal rats, on day 7 they significantly increased as compared with day 2, and on day 14 they significantly decreased as compared with day 7. Stimulation index (SI) ratio of PHA-induced blastogenesis and natural cell-mediated killing (NK) activity were also investigated using splenocytes, thymocytes, and peripheral lymphocytes. The results indicated that immunological competency of splenocytes of tumor bearers was reduced in the early, late, and final tumor-bearing periods, while it was increased in the middle tumor-bearing period. Tumor growth following splenectomy was considered to be controlled by these changes in immunological competency of splenocytes.

[Immunological effect of splenectomy in tumor-bearing rat].

UNLABELLED: Immunologic merit and demerit of splenectomy were studied, using experimental model in rat. ANIMALS: SD rat. Tumor: Metastasizing Rat's Mammary Tumor No. 1 (MRMT-1) originally induced by 3-MC administration to SD rat. Experimental study: Splenectomy was done on day before and after subcutaneous inoculation of 200mg of MRMT-1 at the back of 4 week-old female SD rats. Tumor growth following splenectomy and immunological competency of rat's peripheral lymphocytes, spleen cells and thymus cells was investigated and following results were obtained. When splenectomy was done pre-operatively or on the 2nd or 14th day after tumor inoculation, subsequent tumor growth was inhibited, however, when it was done on the 7th day after the inoculation, tumor enhancement and shortening of survival period were observed. When it was done on the 21st day, tumor growth was almost the same as in the rats without splenectomy. The results of cpm values and SI ratio of PHA-induced blastogenesis, and NK-activity indicated that immunological competency of spleen cells of tumor bearers was reduced during the early tumor-bearing period and the late tumor bearing period, while it was increased in the middle tumor bearing period. Tumor growth following splenectomy was considered to be controlled by immunological competency of spleen cells. Thus, it may not be unreasonable that tumor growth is inhibited on some occasions and it is facilitated on other occasions after splenectomy.

[Antitumor effect of intraperitoneal administration of a streptococcal preparation, OK-432, in carcinomatous peritonitis. I. Experimental study in the rat].

UNLABELLED: The effect of intraperitoneal (ip) OK-432 administration and its mechanism were investigated with experimental tumor of rats. ANIMALS: 4 week-old female SD rats (Slc/SD, closed colony). Tumor: An ascitic tumor, produced by intraperitoneal inoculation of strain cells. These have been established from MRMT-1, which originally was induced by 3-methyl cholanthrene administration. Experimental study: On day 4 or 6 of ip inoculation of 1 x 10(6) tumor cells, 50 KE/kg of OK-432 was administered intraperitoneally and cells were daily examined microscopically. Morphological changes around tumor cells were investigated with Papanicolaou-stained preparations. Following results were obtained: A marked increase in neutrophils was noted in ascitis at 24 hours after ip administration of OK-432; macrophages and lymphocytes appearing later than neutrophils. A subsequent decrease in neutrophils was accompanied by gradual increase in tumor cells. When OK-432 was administered intraperitoneally on day 4 of ip inoculation of tumor cells, aggregation of neutrophils around tumor cells was observed on day 6, and rosette formations around tumor cells with 76 to 10 neutrophils were noted on days 7 and 8. Subsequently tumor cells forming centers of rosettes were found to be destroyed and disappeared. On days 10 to 12, regrowth of tumor cells within incomplete rosette formation was found in ascites. The above reactions were not remarkable, when OK-432 was administered intraperitoneally on day 6 of ip inoculation of tumor cells, and were never observed in untreated cases. These results indicated that cytotoxic effects of ip administration of OK-432 were displayed mainly by rosette formation with neutrophilic cells.