Circadian chemotherapy in cancer patients

Continuous infusion of 5-FU at night was performed for four patients: three had liver metastasis (one with gastric cancer and two with rectal cancer) and one had local recurrence of rectal cancer. The chemotherapy schedule was 400 mg/m2/day 5-FU intraarterial or intravenous infusion from 6:00 p.m. to 6:00 a.m. for five days repeated every 3 weeks. There were one complete response, two partial responses and one with no change. It is expected that the chemotherapy of 5-FU at night will result in a high efficacy and lower toxicity.     

Two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil, cisplatin and cytarabine

We reported two cases of advanced gastric cancer effectively treated with chemotherapy of 5-fluorouracil (5-FU), cisplatin (CDDP) and cytarabine (Ara-C), 5-FU (300-350 mg/body) was given by continuous intravenous infusion. Ara-C (20-40 mg/body) by continuous infusion and CDDP (15-20 mg/body) were added intravenously for 3-6 days. For case 1, epirubicin (30 mg/body) was also given on the first day of each therapy course. Case 1 was a 62-year-old female who had gastric cancer with liver metastasis, ovarian metastasis and peritonitis carcinomatosa. After 3 courses of the chemotherapy, reduction of ovarian metastasis greater than 75% was observed. The value of CA125 decreased from 6,800 U/ml to 527 U/ml and ascites disappeared. Case 2 was a 54-year-old male who had type 3 advanced gastric cancer with multiple liver metastases. He received 6 courses of the therapy. Both primary and metastatic tumors showed over 50% reduction in tumor size. These suggested that this combination therapy was effective for inoperable advanced gastric cancers.     

Hepatic arterial chemotherapy for liver cancer over a period of 8 years

Hepatic arterial chemotherapy was performed for 27 patients with primary (3), metastatic liver cancer (21), and 3 other cases, over a period of 8 years. Chemotherapy was performed by intermittent hepatic arterial infusion of 5-FU or FAM (in case of metastatic tumor from colorectal cancer), FAM (from gastric cancer), and CDDP or Farmorubicin (HCC). Hepatic resection was performed in 10 cases of metastatic tumor from colorectal cancer, and 8 cases of 10 were curative operation. The 5-year survival rates of curative liver resection group, and non-curative liver resection or non-resection group were 57.1% and 12.5%, respectively. As is the case with metastatic cancer from gastric cancer, pancreatic cancer, and hepatocellular carcinoma (HCC), the prognosis was poor except for one CR case of HCC. We concluded that hepatic arterial chemotherapy may be recommended for a curative resected case of liver metastasis from colorectal cancer.     

America: where kids are getting killed

Two cases of liver metastasis from colon cancer were treated by percutaneous ethanol (PEI) and acetic acid (PAI) injection for the recurrent lesion after surgery. Case 1 was a 60-year-old female who received sigmoidectomy with partial hepatectomy, and intraarterial 5-FU infusion was done after surgery. One year later, recurrence of liver tumor was detected, and PEI and PAI were performed for the metastatic lesions of the liver. Tumor regression and histopathological examination revealed coagulative necrosis. The patient died of lung metastasis 2 years and 10 months after treatment. Case 2 was a 58-year-old-male with ascending colon cancer and liver metastasis, who received surgery, and chemotherapy with intraarterial 5-FU infusion was continued. Four months later, recurrence of liver metastasis with elevation of serum CEA was noted. The patient received PEI three times and CEA decreased. Re-operation of hepatectomy revealed complete necrosis at the site of PEI. The patient has been alive for 1 year and 6 months with a new recurrence in the liver and is receiving repeated PEI therapy. PEI and PAI seem to be useful for the treatment of unresectable liver metastasis.     

Intra-arterial preventive chemotherapy for residual liver after resection of hepatic metastasis from colorectal cancer

We treated 18 cases with intra-hepatic arterial infusion chemotherapy after resection of hepatic metastasis from colorectal cancer (June 1991-September 1997). Eight cases were H1, 7 were H2, and 3 were H3. Hepatic lobectomy was done in 3 cases, lobectomy + partial resection in 2 cases, and partial resection in 13 cases. All cases received high-dose intermittent 5-FU infusion (WHF = 5-FU 1,000 mg/m2/5 hrs/w) on an outpatient basis. The total frequency of WHF was 4-54 times (average 29), and total 5-FU doses ranged from 6.0 to 81.0 g (average 40 g). The 1- and 5-year cumulative survival rates were 100% and 77.5% in all patients 100% and 87.5% in H1 group and 100% and 64.3% in H2 + H3 group, respectively. There was no significant difference of survival between the H1 and H1 + H3 groups. The 1- and 5-year recurrence rates in residual liver were 5.9% and 14.4%, respectively. One of 2 cases with residual liver recurrence was resected for metastasis again, and the patient is now in a disease-free state. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect for their survival, not only in H1 group but also in H2 + H3 group.     

Clinical evaluation of anticancer effect of methionine-depleting total parenteral nutrition with 5-fluorouracil and/or mitomycin C

Methionine-depleting total parenteral nutrition (Met-deplete TPN), infusing AO-90 amino acid solution (lacking both L-methionine and L-cysteine) as a sole nitrogen source, showed synergistic effects with several antineoplastics including 5-fluorouracil (5-FU). In the recent multi-center, randomized, controlled study, advanced gastric cancer patients were randomly allocated to RT group and Control group. RT group received AO-90 amino acid solution, while Control group infused Amiparen (commercial methionine and cysteine containing amino acid solution) as protein source for 14 days' TPN with 5-FU and mitomycin C (MMC). The over all clinical response rate (PR+CR) in RT and Control groups were 26.3% and 8.1%, respectively, with significant statistical difference in both values at p = 0.015. Fourteen advanced gastric cancer patients allocated to RT and Control group randomly and received each amino acid as protein source for 7 days TPN with 5-FU administration. All cases were performed gastrectomy without waiting period, and resected material was examined the histological response. In the 7 cases of RT group, grade 2 was seen in 4 cases, grade 1-b in 1, grade 1-a in 1 and grade 0 in 1. In the 7 of Control, 3 cases were grade 1-a and the remaining 4 were grade 0. There were significant differences in both degree and incidence of the histological response at p = 0.016. A stage IV gastric cancer patient with marked liver metastasis received 2 times RT therapy with 5-FU and MMC for 14 days and undertaken gastrectomy after 22 day, waiting period. Resected gastric cancer showed grade 2 to 3 histological response, and the liver metastasis showed marked effect as PR to CR.     

A case report: multiple liver metastasis of gastric cancer responding to intraarterial infusion of MTX and 5-FU

In a 63-year-old male patient with gastric cancer having multiple liver metastases, the metastatic lesions responded well to postoperative staggered intraarterial infusion therapy with MTX and 5-FU. The intraarterial infusion therapy was administered once a week. A total of 5 courses of this therapy produced marked regression of liver metastases and remarkable necrosis. The effect was thus rated as PR. The patient is healthy and has been successfully rehabilitated. His dose is oral 5-FU (200 mg x 2).     

Combination chemotherapy of continuous infusion 5-fluorouracil and daily low-dose cisplatin in advanced gastrointestinal and lung adenocarcinoma

Continuous intravenous infusion (c.v.i.) of 5-fluorouracil (5-FU) plus daily low-dose cisplatin (CDDP) was evaluated in 45 patients with advanced and recurrent unresected colorectal, lung, gastric and pancreatic adenocarcinoma. 5-FU was given at a dose of 320 mg/m2/day, c.v.i. for 4 weeks, and CDDP between 3.5 to 7 mg/m2/day, infused for one hour five times a week for 4 weeks. Patients received 1 to 3 cycles of treatment (average 1.5 cycle). Pancreatic cancer cases needed longer treatment periods (2.25 cycles). The response rate of colorectal cancer cases was 57.7% (15/26), pancreas cancer 40%, gastric cancer 62.5%, and lung cancer 66.7%. The overall response rate was 57.8%. No severe side effects occurred in any of these cases. These data indicate that this combination 5-FU + daily low-dose CDDP chemotherapy is effective in the treatment of advanced gastrointestinal and lung adenocarcinoma.     

The preventive effect of weekly high-dose 5-FU infusion (WHF) after resection of hepatic metastasis from colorectal cancer

Hepatic metastasis is often found even after resection of hepatic metastases from colorectal cancer. This implies that the micrometastasis already existed in residual liver when the resection was performed, and so complete recovery with resection alone is rare. We have been using a weekly high-dose 5-FU HAI (WHF = 5-FU 1,000 mg/m2/5 hrs/qw) since 1991, which has preventive effects for metastasis in residual liver as compared to a group treated without infusion chemotherapy. Hepatectomy was performed in 30 of 113 cases of hepatic metastasis from colorectal cancer during the past 16 years. For comparison, we divided the 30 cases into group A1 (16 cases H1:12, H2:4), which received hepatectomy only, and group A2 (14 cases H1:8, H2:4, H3:2), which additionally received infusion chemotherapy. The 1- and 3-year (cumulative) survival rates were 64.6% and 32.3% in group A1, and 100% and 75.3% in group A2 respectively in which the treatment outcome was significantly higher. The 1- and 3-year recurrence rates were 41.7 and 66.3 in group A1, and 8.3% each in group A2, respectively, which reveals that metastasis in residual liver was controlled in group A2. Other metastases were seen in lung (6 cases), bone (2 cases), hepatic hilar lymph node (3 cases), brain (1 case) and local (3 cases) in group A1, while only one metastasis in each brain and locally was seen in group A2 so far. WHF after resection of hepatic metastasis from colorectal cancer has a preventive effect not only for the recurrence in residual liver but also for other metastases. Therefore, as improvement in the survival rate is expected.     

Intraarterial chemotherapy via reservoir system for far-advanced bladder and prostate cancer

A clinical study was performed on the efficacy of intraarterial chemotherapy using reservoir system for far-advanced urological malignancy. The reservoir system was indwelled in the femoral subcutaneous layer using Seldinger's method. Fifteen cases with inoperable complicated advanced bladder cancer and ten cases with postoperative local recurrent bladder cancer received intraarterial chemotherapy using the reservoir system. Then, 23 cases with local relapsed prostate cancer and two cases with endocrine-resistant prostate cancer received chemotherapy. The administered anti-cancerous agents were methotrexate, cis-platinum and adriamycin, and 5-FU or carboplatin were administered as maintenance therapy. The mean courses of chemotherapy were six for bladder cancer and four for prostate cancer. During stabilization of the local lesion, no distant deterioration was recognized. Overall clinical efficacy was as follows: PR:18 cases and NC:7 cases for bladder cancer; then, PR:11 cases and 14 cases for prostate cancer. The median duration of stabilization was as follows: 23 months for bladder cancer and 12 months for prostate cancer. Complications were fewer than with systemic chemotherapy.     

Prognosis of hepatic metastasis from colorectal cancer following hepatic resection and arterial infusion chemotherapy--assessment from the percentage of tumor involved area

Prognosis of hepatic metastasis from colorectal cancer following hepatic resection and arterial infusion chemotherapy was studied from the percentage of tumor involved area (PTIA). The PTIA was calculated by the following formula: sigma S'/sigma S, with S' as the tumor area and S as the liver area on each CT slice. The subjects were 25 cases of hepatic resection (HR), and 31 cases of hepatic arterial infusion chemotherapy (HAI). The PTIA of the cases of HR and that of HAI was 1.5 to 25.9% and 0.8 to 31.3%, respectively. For comparison, all cases were divided into group A, which was not more than 10% of the PTIA, and group B, which was more than 10% of the PTIA. In the cases of HR, the prognosis of group A was significantly better than that of group B (p < 0.05). In the cases of HAI, the prognosis of group A was better than that of group B. Even in group A, the prognosis of the cases of HR was significantly better than that of HAI (p < 0.05). These results suggest that the PTIA in the cases of HR and HAI for metastasis from colorectal cancer is important factor which reflects the prognosis.     

Preoperative neoadjuvant chemotherapy with a combination of 5-fluorouracil, adriamycin and cisplatin (FAP) for advanced esophageal cancer invading trachea or main bronchus

Conventional irradiation and systemic chemotherapy is scarcely effective for advanced esophageal cancer invading trachea or main bronchus. Therefore, to reduce the area of invasion and suppress distant metastasis, we have preoperatively treated 4 patients suffering from advanced esophageal cancer invading the trachea or main bronchus by neoadjuvant chemotherapy (FAP) as follows: 2 times every 4 weeks, CDDP 100 mg and ADR 50 mg on day 1 and continuous infusion of 5-FU 1,000 mg/day for 7 days. The response rate (PR) was 75% (3/4). In 2 of 4 patients (50%), no cancer cells except broad fibrosis were detected histologically in the region of the trachea or main bronchus suspected to be invaded. There was no severe complication. This FAP regimen is suspected to be useful chemotherapy for advanced esophageal cancer.     

A study of various complications in arterial infusion chemotherapy

Complications of arterial infusion chemotherapy were analyzed in 261 cases from December 1983 to December 1993 in our department. Their complications involved nausea and vomiting (40.6%), bone marrow suppression (33.3%), liver dysfunction (20.3%), gastric and duodenal ulcer (9.6%) and so on. Complications involving an implantable device were hepatic arterial obstruction (29.1%), reservoir obstruction (5.7%), dislocation of catheter (4.6%), infection of catheter (3.8%), and obstruction of catheter (1.9%). In another cases with hepatic arterial obstruction, we performed arterial infusion in another artery as a bypass or stopped the infusion. In cases with obstruction of catheter not able to be reopened, we reinserted the catheter. An obstructed and/or infected reservoir was removed or replaced. Nausea and vomiting were found in 46.3% of FAM arterial infusion method (FAM) cases, in 53.3% of 5-FU persistent arterial method (5-FU) + FAM cases, and in 40.5% of intermittently persistent arterial method (IP) cases. Gastric and duodenal ulcer were noted in 9.8% of FAM, 13.3% of 5-FU + FAM, and 8.1% of IP cases. There were no significantly statistical differences between the methods. Hepatic arterial obstruction predominantly occurred in 32.4% of IP and 26.7% of 5-FU + FAM and bone marrow suppression was predominant in cases in which ADM was used. The duration of obstruction after administration was 154.0 +/- 117.4 days on average (21-455 days). Complications of hepatic arterial infusion chemotherapy are based on various causes which can be managed for prevention. We intend to enhance safety and assure the greater effectiveness of hepatic arterial chemotherapy.     

The role of lipogenesis in the development of obesity and diabetes in Israeli sand rats (Psammomys obesus)

In order to optimize the therapeutic index of combining etoposide, epirubicin, cisplatin, 5-fluorouracil (5-FU), leucovorin (EEPFL) chemotherapy in the treatment of advanced gastric cancer, a trial of a novel schedule of weekly administration was conducted. Weekly EEPFL treatment consisted of a concomitant boost of etoposide 40 mg m(-2) i.v. over 30 min, epirubicin 10 mg m(-2) i.v. over 5 min to a backbone regimen, weekly PFL chemotherapy with cisplatin 25 mg m(-2), 5-FU 2200 mg m(-2), leucovorin 120 mg m(-2) given simultaneously by 24-h i.v. infusion. Response, survival and toxicity were evaluated. Forty-two patients were studied. Median age was 69 (range 31-84) years. Twenty-six per cent of patients showed complete response and 45% partial response. The overall response rate was 71% (95% confidence interval 58-84%). For a total of 507 weekly EEPFL cycles delivered, the incidence of grade 4 leucopenia was 1% of cycles. One patient died of neutropenia septicaemia. There was no other grade 4 toxicity. Grade 3 and 2 leucopenia occurred in 7% and 14% of cycles. The incidence of grade 3 and 2 mucositis was 1% and 3% of cycles. Grade 3 and 2 diarrhoea occurred in 0.4% and 1.6% of cycles. Overall median survival was 10 months (range 3-41+ months). Weekly EEPFL chemotherapy is an effective regimen with tolerable toxicities in the treatment of advanced gastric cancer. A randomized controlled clinical trial to formally assess the efficacy and benefit of EEPFL chemotherapy is under way.     

Retrospective comparison of infusional 5-fluorouracil, doxorubicin, and mitomycin-C (modified FAM) combination chemotherapy versus palliative therapy in treatment of advanced gastric cancer

About one-third of patients with gastric cancer are unresectable at the time of diagnosis. Their median survival is < 6 months, with a grave prognosis. The purpose of this study was to assess the efficacy of a modified FAM (mFAM) regimen in advanced gastric cancer. We retrospectively reviewed the clinical records of 409 advanced gastric cancer patients who had not received curative surgery. Among 409 patients, 202 patients were treated with an mFAM regimen (infusional 5-FU + doxorubocin + mitomycin-C), and 207 patients received no chemotherapy (control group). No differences were found in clinical parameters between the two groups. The 1-year survival rates were 34.1% for the mFAM-treated group and 22.5% for the control group (p = 0.0135). In subset analysis, a higher 1-year survival rate was demonstrated in patients with mFAM and palliative surgery. Of the 154 evaluable patients in the mFAM-treated group, the response rate was 17.5%. In these patients, median response duration was 30 weeks, and progression-free survival was 23 weeks. Overall toxicity of mFAM regimen was relatively tolerable and reversible. In conclusion, FAM combination chemotherapy, which has been used as a standard therapy, prolonged survival after modification of the administration schedule and combination with palliative surgery. A prospective randomized study is warranted to confirm this conclusion from our retrospective study.     

Double mitral valve orifice. Two-dimensional and Doppler echocardiographic diagnosis

A thirty three-year-old male complaining of vomiting was diagnosed as having type 3 advanced gastric cancer of upper stomach and multiple liver metastasis, and had undergone total gastrectomy. The conclusive stage was P2H2n4se stage IVb. Intraoperatively, ethanol injection was performed for the liver metastasis under ultrasonography, and CDDP 100 mg was injected into the intra-abdominal cavity. Postoperative adjuvant therapy was added using oral fluorouracil and OK-432. Then we utilized FP chemotherapy (consisting of 5-FU and cisplatin) and radiotherapy for the bone metastasis. The patient survived 4 years and 4 months with good quality of life.     

A new method of high-dose intraarterial chemotherapy of the pancreas using direct hemoperfusion (DHP) under portal venous isolation (PVI)

Surgical resection for pancreatic cancer is severely limited by the extent of the disease at the time of diagnosis. Chemotherapy has been the treatment of choice for unresectable cases. We developed a new method of intraarterial chemotherapy for pancreatic body and tail cancers using direct hemoperfusion (DHP) under portal venous isolation (PVI). Adriamycin (ADR, 3 mg/kg) was infused into the splenic arteries of mongrel dogs for 5 min after clamping off blood flow to the stomach and the duodenum. In group A (n = 5), this was simply done, and in group B (n = 5) the portal venous blood was isolated by clamping at the porta hepatis and pumped through the DHP circuit to the jugular vein for 20 min from the start of drug infusion. The peak systemic level (microgram/ml) of group B (0.78 +/- 0.03) was significantly reduced by PVI.DHP as compared to that of group A (3.49 +/- 1.15, P < 0.01). The pancreatic tissue levels (microgram/g. tissue) 30 min after drug infusion of group A (61.2 +/- 13.4) were slightly lower than those in group B (88.9 +/- 27.8), although not statistically significant. However, tissue levels of group B in the liver (27.3 +/- 9.2) and heart (1.8 +/- 0.8) were significantly lower than those of group A (liver; 52.3 +/- 18.5, heart; 4.9 +/- 0.6, P < 0.05). In conclusion, PVI.DHP achieved a significant reduction in systemic drug exposure during intraarterial chemotherapy. Therefore, we consider that this system will allow dose escalation of ADR during intraarterial chemotherapy for pancreatic body and tail cancers.     

Pitfalls of processed pseudogenes in RT-PCR

The patient was a 72-year-old female who had Stage IVb advanced gastric cancer with Virchow's and paraaortic lymph node metastases. She was considered nonresectable and placed on neoadjuvant chemotherapy consisting of low-dose CDDP and 5-FU. After 1 course of administration, Virchow's metastasis disappeared, and the tumor was remarkably reduced in size. However, this chemotherapy was interrupted by toxicity of grade 3 appetite loss, nausea and vomiting, so that total gastrectomy and splenectomy were performed, which were non-curative operation because of paraaortic lymph node metastases. Histopathological examination of the section of the primary tumor revealed that cancer cells had almost disappeared, and only a few atypical cells remained in the granulation tissue. Eleven months after the surgery, there has been no progression of Virchow's and paraaortic lymph node metastases. Combination chemotherapy of low-dose CDDP and 5-FU appears useful as an inductive approach to advanced gastric cancer.     

Sequential intrahepatic fluorodeoxyuridine and systemic fluorouracil plus leucovorin for the treatment of metastatic colorectal cancer confined to the liver

PURPOSE: Extrahepatic metastasis represents a frequent pattern of disease progression when fluorodeoxyuridine (FUDR) is given by the intraarterial route for the treatment of unresectable colorectal liver metastases. Systemic fluorouracil (5-FU) plus leucovorin was added to intrahepatic FUDR to prolong the duration of disease control. METHODS: Only patients with colorectal cancer who had evidence of unresectable metastases confined to the liver were eligible. Laparotomy was performed to establish arterial perfusion of the liver. Cycles of intrahepatic FUDR followed by a 1-week rest period then intravenous chemotherapy with 5-FU plus leucovorin were administered until maximal regression of hepatic metastases. Maintenance chemotherapy with 5-FU plus leucovorin was then given until disease progression. RESULTS: Fifty-seven patients entered this trial; four patients (7%) were ineligible and 13 (23%) did not receive any chemotherapy on study because of findings at laparotomy. The 40 eligible patients who began chemotherapy are included in the statistical analyses. Twenty-five patients (62% of those who received chemotherapy) experienced regression of liver metastases. The median time to tumor progression was 9 months, but only 3% remained progression-free at 24 months. The median survival duration was 18 months. Toxicity was tolerable with no cases of biliary sclerosis. One treatment-related fatality due to sepsis was observed. CONCLUSION: Although short-term treatment results appear to be somewhat better than we have previously observed with intrahepatic FUDR alone, the sequential regimen did not have an impact on long-term, progression-free survival in patients with unresectable liver metastases. We are now investigating this regimen as surgical adjuvant therapy in selected patients following hepatic metastasectomy where this aggressive approach might have a greater therapeutic effect in the minimal residual disease setting.     

Induced hypertensive chemotherapy with angiotensin-II for liver metastases from gastric cancer

The theoretical purpose of induced hypertensive chemotherapy used together with injection of Angiotensin-II is to increase the delivery of anticancer drug to the target tumor tissue by increasing blood flow in the tumor. Angiotensin-II (0.1 mg) was dissolved in 50 ml of normal saline, and given through a peripheral vein by a microinfusion pump. When systolic pressure rose to about 140 to 150 mmHg, Mitomycin C (10 to 20 mg/body) was given for 10 minutes via implanted port, whose tip was located in hepatic artery, followed by continuous infusion of 5-FU at 250 mg/day for 5 days. Response could be measured in 4 of all cases (66.7%). CR was found in 2 and PR in 2. Bone metastases or systemic lymph node metastases occurred after a few months in one CR case and one NC case. We concluded that this mode of chemotherapy was a useful measure for the treatment of liver metastases from gastric cancer.