PLA2 (group IIA phospholipase A2) as a prognostic determinant in stage II colorectal carcinoma

Background: Approximately 30% of all colorectal cancer (CRC) patients are diagnosed with stage II disease. Adjuvant therapy is not widely recommended. However, it is well established that a subgroup of patients with stage II are at high risk for recurrence within their lifetime and should be considered for adjuvant chemotherapy. The present work was designed to assess the value of group IIA phospholipase A2 (PLA2) as a predictor of disease outcome in stage II CRC patients with long-term follow-up.Patients and methods: The present study comprises a series of 116 patients who underwent bowel resection for stage II CRC during 1981–1990 at Turku University Hospital. Archival paraffin-embedded CRC tissue samples were used to prepare tissue microarray blocks for immunohistochemical staining with PLA2.Results: Fifty-five percent of all tumors were positive for PLA2. There was no significant correlation between PLA2 expression and age, sex, depth of invasion and lymph node status. In Kaplan–Meier survival analysis, there was a significant (P = 0.010) difference in disease-free survival (DFS) between patients with negative tumors (longer DFS) and those with positive tumors. The same was true with disease-specific survival (DSS), patients with PLA2-negative tumors living significantly longer (P = 0.025). In multivariate (Cox) survival analysis, however, PLA2 was not an independent predictor of DFS or DSS. In subgroup analysis, the right-sided tumors with negative PLA2 staining had remarkably better prognosis (P = 0.010) than PLA2-positive left-sided tumors.Conclusions: Quantification of PLA2 expression seems to provide valuable prognostic information in stage II CRC, particularly in selecting the patients at high risk for recurrent disease who might benefit from adjuvant therapy.     

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.     

A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer: a cooperative study group trial (group B)

A late phase II clinical study of RP56976 (docetaxel) in patients with advanced or recurrent gastric cancer was performed to evaluate the anti-tumor activity and clinical toxicity as a multicenter cooperative trial. Docetaxel was administered intravenously at a dose of 60 mg/m2 every 3-4 weeks. Of 72 patients enrolled, 63 patients were eligible and 59 patients were evaluable for response. The anti-tumor effects obtained complete response (CR) in one patient partial response (PR) in 13, minor response (MR) in 3, no change (NC) in 20, and progressing disease (PD) in 22 patients. The overall response rate in 59 patients was 23.7% (14/59). For 14 CR or PR cases, a response appeared 10 to 107 days (median 33.5 days) and 1 to 8 (median 2) times of dosing after the initial administration. The response rate was 9.5% in the primary tumor, 31.3% livers, 50.0% abdominal tumor, and 24.1% lymph nodes, respectively. The major adverse reactions were gastrointestinal symptoms including nausea/vomiting, anorexia, fatigue, alopecia and fever. Leukocytopenia and neutrocytopenia were also observed with a high incidence, but they recovered after 8 days from the nadir. The results show that docetaxel is an effective anti-tumor agent for advanced or recurrent gastric cancer. It is necessary to conduct another clinical trial by concomitant administration with other anti-tumor agents.     

Phase II trial of mitoxantrone in advanced gastric cancer

A Phase II trial of mitoxantrone was performed in patients with advanced adenocarcinoma of the stomach. All patients had measurable or evaluable disease, and none had received prior chemotherapy. Mitoxantrone was administered intravenously at a dose of 14 mg/m2 every 3 weeks. The major toxicity seen was myelosuppression. The drug was, in general, well tolerated. No major objective responses were seen. We conclude that mitoxantrone has less than 20% activity in this patient population. No further studies are planned.     

Super-extended (D3) lymphadenectomy in advanced gastric cancer

Purpose

To analyze our experience with D3 lymphadenectomy in the treatment of advanced GC with specific reference to post-operative morbidity and mortality, incidence of para-aortic node (PAN) metastases, and long-term prognosis.

Methods

Short- and long-term results of D3 lymphadenectomy were analyzed in 286 patients with advanced GC.

Results

PAN metastases were demonstrated in 37 patients. PAN involvement was significantly higher in upper third tumours (29%) compared to middle and lower third (7%; P < 0.001). Eighty patients developed post-operative complications, being pulmonary disorders (6%), abdominal abscesses (4.5%) and pancreatic fistulas (3%) the most frequently observed. In-hospital mortality was 2%. Overall 5-year survival rate for R0 pT2-4 patients was 52%. When considering survival in relation to nodal involvement, both pN3 and non-regional lymph node metastases (M1a) patients showed a chance of long-term survival: 5-year survival was 31% for pN3 and 17% for M1a cases. Furthermore, the 5-year survival rate was remarkably high (about 60%) even in pN2 and pN3 subsets when no serosal invasion (pT2) was demonstrated.

Conclusions

D3 lymphadenectomy could be further explored in specialized centers for curative surgery of advanced GC, especially for upper third tumours, providing that an acceptable morbidity and no increase in mortality can be offered.     

A multicenter phase II study of TAS-102 monotherapy in patients with pre-treated advanced gastric cancer (EPOC1201)

AimAmerican phase I studies have reported that the recommended dose of TAS-102 (trifluridine/tipiracil) was 25 mg/m² twice a day (b.i.d.), although this schedule did not provide clinically relevant improvements in a phase II study of advanced gastric cancer (AGC). However, a pivotal phase III study revealed that TAS-102 at 35 mg/m² b.i.d. provided a clinically relevant improvement in overall survival (OS) among patients with metastatic colorectal cancer. Therefore, we re-evaluated the efficacy, safety, and pharmacokinetic parameters of TAS-102 at 35 mg/m² b.i.d among Japanese patients with AGC.MethodsAll patients had undergone one or two previous chemotherapy regimens that contained fluoropyrimidine, platinum agents, and taxanes or irinotecan. The primary end-point target was a disease control rate (DCR) of ≥50% after 8 weeks of the 35 mg/m² b.i.d. schedule.ResultsTwenty-nine patients were assessable after completing the 35 mg/m² b.i.d. schedule. The investigator-determined DCR was 65.5% (95% confidence interval [CI], 45.7–82.1%) and the independent central review's DCR was 51.9% (95% CI, 31.9–71.3%); both results exceeded the primary end-point target. The median progression-free survival and OS were 2.9 months (95% CI, 1.1–5.3 months) and 8.7 months (95% CI, 5.7–14.9 months), respectively. The grade III/IV adverse events included neutropenia (69.0%), leucopaenia (41.4%), anaemia (20.7%), and anorexia (10.3%). No AGC-specific toxicities were detected.ConclusionsThe 35 mg/m² b.i.d. dose of TAS-102 provided positive efficacy and an acceptable toxicity profile in patients with AGC. A randomised, double-blind, placebo-controlled, phase III study is ongoing to validate these findings.Clinical trial registration numberUMIN000007421     

Pemetrexed and cisplatin in patients with advanced gastric cancer: a Korean cancer study group multicenter phase II study

BACKGROUND: Pemetrexed is a multitargeted antifolate enzyme inhibitor, which has activity against a variety of tumors, including advanced gastric cancer (AGC). The aim of this study was to assess efficacy and safety of pemetrexed plus cisplatin (PemCis) combination in the treatment of AGC in Korean patients. PATIENTS AND METHODS: This was a multicenter, single arm, open label study. Patients with no prior palliative chemotherapy received pemetrexed 500 mg/m(2) and cisplatin 75 mg/m(2) day 1, every 3 weeks plus folic acid and vitamin B(12) supplementation. Response rate was assessed according to response evaluation criteria in solid tumors (RECIST) criteria. RESULTS: Of the 50 patients evaluable for efficacy, 13 had partial response for an overall response rate of 26% (95% CI, 14.6-40.3%) and 15 (30%) had stable disease. Median time to progression was 2.8 months (95%CI, 2.2-4.4 months), and median overall survival was 6.6 months (95% CI, 4.8-10.4 months). Of the 51 patients evaluable for safety, the most frequent NCI-CTC grade 3/4 toxicities were neutropenia in 49% of patients (25% of cycles) and anorexia in 10% of patients (4% of cycles). CONCLUSION: PemCis has a modest activity and acceptable toxicity profile in patients with AGC. Clinical trials with different combinations and dose regimens are, therefore, warranted.     

Phase II trial of 5-fluorouracil,adriamycin and cisplatin (FAP) in advanced gastric cancer

Summary Twenty patients (15 male, 5 female) with nonresectable gastric adenocarcinoma were treated with FAP (5-fluorouracil 300 mg/m² IV on days 1–5, adriamycin 50 mg/m² IV on day 1, cisplatin 20 mg/m² IV on day 1–5). Each course was repeated every 21 days. Eighteen patients were evaluable for response. The median age was 51 years, the range extending from 34 to 68. None had undergone chemotherapy. The median Karnofsky performance score was 80%. Nine (50%) partial responses (PR) and eight (44%) cases of stable disease (SD) were observed. One patients showed progression of the disease and died after 6 months. The median duration of response was 6+ months for PR and 6 months for SD. The median survival was 12 months. FAP toxicity was moderate, with the median WBC nadir 3.2×10⁹/l (range 0.7–4.2). One patient in PR died of septicemia. Nausea and vomiting were not dose-limiting. Neuropathy was mild in four and moderate in two patients. This FAP combination appears to be as effective with respect to response rate and duration as reported for 5-fluorouracil, adriamycin and mitomycin C (FAM).     

A pilot phase II study of capecitabine in advanced or recurrent gastric cancer

OBJECTIVES: To evaluate the efficacy and safety of capecitabine in patients with advanced or recurrent gastric cancer, we conducted a pilot phase II study in Japan. METHODS: Patients with advanced or recurrent gastric cancer were given oral capecitabine 828 mg/m(2) twice daily for 3 weeks, followed by 1 week of no treatment. Two or more cycles were administered. From July 1996 to December 1997, 32 patients were enrolled in the study. The response to capecitabine was evaluated in 31 patients, excluding 1 found to be ineligible. RESULTS: The overall response rate was 19.4% (6/31, 95% confidence interval: 7.5-37.5%). The median duration of response was 124.5 days, the median time to disease progression 85.0 days, and the median survival time 247.5 days. Drug-related adverse events of grade 3 or higher were infrequent: in 2 patients (6.3%) total bilirubin concentration increased, and 1 patient (3.1%) each had elevation of GOT, anemia, lymphopenia, increased creatinine, and hand-foot syndrome. No patient had gastrointestinal toxicity of grade 3 or higher. CONCLUSION: Capecitabine was suggested to be safe and effective in the treatment of advanced or recurrent gastric cancer. Further phase II studies of capecitabine on a large scale are warranted.     

A phase II study of SM-5887 for advanced gastric cancer]

A phase II clinical trial of SM-5887, a new totally synthesized anthracycline derivative, was carried out in 13 patients with inoperable or recurrent gastric cancer. No patient had been given anthracycline previously. SM-5887 was administered by I.V. bolus with a dose of 100 mg/m2 every three weeks. Twelve of 13 cases were eligible and evaluable for the response. Of the 12 evaluated cases, 6 showed no change (NC), including one minor response (MR). The remaining 6 cases showed progressive disease (PD). Adverse effects were relatively mild in most cases and included anemia, leukocytopenia, thrombocytopenia, nausea/vomiting, phlebitis, hair loss and fever. Among them, leukocytopenia was observed most frequently.     

Phase II study of cisplatin in advanced esophageal cancer and gastric cancer

Twenty-four patients with advanced gastric cancer and 4 patients with advanced esophageal cancer were treated with cisplatin at a dose of 80-100 mg/m2 for one day or 10-20 mg/m2 for 5 consecutive days every 3-4 weeks. As for gastric cancer, 21 of 24 were evaluable for this study according to the criteria of the Japan Society for Cancer Therapy. Four of 21 patients (19%) showed partial response (PR), 7 displayed no change (NC), and 10 evidenced progressive disease (PD). Among 4 PR cases, only one had effective primary lesion. As for esophageal cancer, all 4 patients were evaluable, while 2 showed no change (NC) and another 2 exhibited progressive disease (PD). Gastrointestinal toxicity occurred in 20 patients despite the use of anti-emetic drugs. Nephrotoxicity and hematological toxicity were observed in 14 patients and 22 patients, respectively. These did not impede the continuous treatment except one case of hematological toxicity. It was concluded that cisplatin is more effective for the metastatic lesion of gastric cancer than primary lesion.     

Overexpression of group II phospholipase A2 in human breast cancer tissues is closely associated with their malignant potency.

Membrane-associated phospholipase A2 (M-PLA2) is an enzyme that hydrolyses the sn-2 fatty acyl ester bond of phosphoglycerides. We measured M-PLA2 concentration in tissue extracts from 325 human breast cancers using a specific radioimmunoassay recently developed. Correlation analyses between the tissue concentration of M-PLA2 and clinicopathological factors showed that the enzyme level was significantly higher in patients with distant metastasis than in those without. In addition, M-PLA2 concentration was significantly higher in scirrhous carcinoma than in other histological types. No significant association was found between M-PLA2 concentration and age, menstrual status, tumour size, histological grade, vessel involvement or oestrogen receptor (ER) and progesterone receptor (PR) status. The expression of M-PLA2 mRNA was examined in a fibroadenoma, a stage IV breast cancer and its metastatic site of skin. Northern blot analysis showed a clear hybridisation band corresponding to M-PLA2 mRNA in both primary breast cancer and its metastatic site, while the fibroadenoma expressed a faint band corresponding to M-PLA2 mRNA. Breast cancer patients with high M-PLA2 concentrations exhibited significantly shorter disease-free and overall survival than those with low M-PLA2 concentration at the cut-off point of 5 ng 100 mg-1 protein, which was determined in a separate study. In multivariate analysis, M-PLA2 was found to be an independent prognostic factor for disease recurrence and death in human breast cancer. The possible significance of M-PLA2 expression in human breast cancer tissue is discussed.     

N-(Phosphonacetyl)-l-aspartate (PALA) in advanced breast cancer: a phase II trial of the EORTC breast cancer cooperative group

Twenty-nine evaluable patients with extensively pretreated breast cancer received PALA, a new pyrimidine antimetabolite. The drug was given by intravenous infusion over 60 min, at a daily dose of 2.5 g/m² for 2 consecutive days. Courses were repeated at 2-week intervals and doses were escalated to toxicity. Two objective partial remissions were observed, lasting for 3 and 4.5 months respectively. Toxic effects were dose-related and consisted mainly of mucocutaneous manifestations, i.e., skin rashes, stomatitis, diarrhea, conjunctivitis and corneal ulcerations. Evidence of antitumor potential in far-advanced disease and lack of myelosuppression point to the need for additional trials of PALA in a more favorable selection of patients with breast cancer.     

PMC (pharmacokinetic modulating chemotherapy) for advanced gastric cancer

We performed pharmacokinetic modulating chemotherapy (PMC) postoperatively in patients with advanced gastric cancer and examined its antitumor and the side effects. Nineteen patients with advanced gastric cancer (all were above Stage II) were treated: 10 had undergone total gastrectomy and 9 distal gastrectomy. UFT (400 mg/day) was orally administered daily and a continuous infusion of 5-FU (600 mg/m2/24 hr) was given once a week. The average observation period was 14.26 months (4-30 months). All patients with Stage II or III disease have survived, but two patients with Stage IV disease died. One patient received insufficient PMC and the other had a liver metastasis. Two patients experienced Grade 3 inappetence, but all other side effects were Grade 2 or lower and the incidence was less than 25%. In conclusion. PMC has tolerable side effects and may be effective in postoperative chemotherapy for advanced gastric cancer.     

A phase II trial of ftorafur: adriamycin and mitomycin-C (FAM II) in advanced gastric adenocarcinoma.

Fifteen patients with advanced gastric cancer were treated with the combination of Ftorafur, Adriamycin and mitomycin-C (FAM II). Three patients showed partial responses, in five the disease remained stable for at least 3 months and seven showed progression while on treatment. All responding patients showed survival in excess of 12 months. Hematologic toxicity was of only moderate severity. Median white count nadir was 3500 cells/mm3 and median platelet nadir was 187,000 cells/mm3. Four patients had white count nadirs from 2000--2500 cells/mm3 and three had nadirs from 500--1500 cells/mm3; also there were four with platelet nadirs less than 100,000/mm3. However, no drug-related infections occurred and no platelet transfusions were required. The major non-hematologic toxicities of the regimen were nausea, vomiting, dizziness, vertigo, and rhinorrhea. These toxicities were limiting and resulted in termination of the trial because of poor patient acceptance and the failure of the combination to exhibit a therapeutic advantage over the similar combination (FAM) that employed weekly 5-fluorouracil in place of Ftorafur.     

Phase II trial of etoposide, doxorubicin (Adriamycin), and cisplatin (EAP regimen) in advanced gastric cancer

Ten previously untreated patients with gastric cancer were treated with etoposide, 120 mg/m2 intravenously (i.v.) on days 4, 5, and 6, Adriamycin, 20 mg/m2 i.v. on days 1 and 7, and cisplatin, 40 mg/m2 i.v. on days 2 and 8 (EAP). Etoposide, 240 mg/m2 on days 4, 5, and 6, was administered orally instead of intravenously in alternating cycles, and pharmacokinetic studies were performed in those who had previously undergone gastrectomy or who had tumor infiltrating the stomach to determine oral bioavailability. Nine patients had advanced measurable gastric cancer, and one patient had an elevated carcinoembryonic antigen after surgery for synchronous gastric and colon cancer. The median age was 54 years (range 38-69), and the median Eastern Cooperative Oncology Group (ECOG) performance status was 2 (range 0-3). Nine of 10 patients had poorly differentiated adenocarcinoma. Twenty-four cycles were administered to 10 patients, and hematologic data were available for 23 courses. ECOG grade 4 neutropenia and thrombocytopenia developed in 19 (83%) and 8 (53%) courses, respectively. Thirteen courses (54%) were complicated by fever requiring parenteral antibiotics. Two patients (20%) died due to neutropenic sepsis. The profound myelotoxicity observed in our study prompted us to terminate the investigation prior to completing accrual. The oral bioavailability of etoposide was 21% and 36% in the two patients who had had prior gastrectomy.(ABSTRACT TRUNCATED AT 250 WORDS)     

Phase II trial of UFT in advanced colorectal and gastric cancer

A phase II trial of continuous oral therapy with UFT, a combination of uracil and the 5-fluorouracil analogue 1-(2-tetrahydrofuryl)-5-fluorouracil (Futraful, Ftorafur), was conducted in 40 patients with advanced colorectal cancer and 18 patients with advanced gastric cancer. Six partial responses were seen in the 36 evaluable patients with colorectal cancer (response rate 16.6%; 95% confidence limits 6.4-32.8%), and one partial response was seen in the 16 evaluable patients with gastric cancer (response rate 6%; 95% confidence limits 0.27-30.2%). The overall toxicity of the treatment was low, and all patients were treated as outpatients. The results suggest that oral UFT has comparable activity to standard regimes of 5-fluorouracil, and because of the convenience of oral administration is a useful therapy in the management of patients with advanced colorectal cancer.     

A phase II study of carboplatin plus gemcitabine in advanced non-small-cell lung cancer (NSCLC): a hoosier oncology group study

The purpose of this study was to evaluate the toxicity and determine the response rate, duration of remission, and survival using gemcitabine plus carboplatin in non-small cell lung cancer (NSCLC). This was a phase II study of gemcitabine and carboplatin in chemotherapy-naive patients with advanced NSCLC and Karnofsky Performance Status of at least 80. Gemcitabine was administered intravenously at 1,000 mg/m2 weekly for 3 weeks followed by 1 week rest. Carboplatin was administered immediately after gemcitabine at an area under the curve (AUC) of 5 given intravenously on day 1 of an every-4-week cycle. Seven patients were entered in the study and five were evaluable for toxicity. The median age of patients was 68 years (range, 52-72). The protocol was prematurely terminated because of severe and unexpected hematologic toxicity. Grade 3-4 thrombocytopenia was observed in four of the first five patients. These toxicities were all observed with the first course of chemotherapy. There were no objective responses seen. Median survival time was 130 days. Carboplatin plus gemcitabine was a logical combination. However, because of the severe thrombocytopenia associated with this regimen, we do not recommend this two-drug combination in the dose and schedule used in this study.