Retrospective study as first-line chemotherapy combined anti-VEGF antibody with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer.

BACKGROUND/AIM: Combination chemotherapies of oxaliplatin or irinotecan with fluoropyrimidine and molecular target drug were reported to be active in several clinical studies and so regarded as a first-line standard therapy for unresectable or metastatic colorectal cancer. However, the incidence of adverse events is not so low. We investigated the efficacy and safety of chemotherapy combined bevacizumab with fluoropyrimidine as a first-line treatment for frail patients. METHODS: Twenty-six patients with unresectable or metastatic colorectal cancer who were treated with first-line chemotherapy combined bevacizumab with S-1 or 5FU/LV (modified Roswell Park Memorial Institute regimen) at our hospital between October 2007 and December 2010 were retrospectively investigated. RESULTS: The median age was 72 years (range 66-84). Performance status was 0, 1 and 2 in 8, 17 and 1 patient, respectively. The primary lesion was located in the colon in 14 patients and in the rectum in 12. Twenty patients were with resection of the primary lesion and 6 were without, 8 were with postoperative adjuvant chemotherapy and 18 were without. The number of metastasized organs was 1, 2 and 3 in 17, 9 and 0 patients, respectively. The liver, lung, lymph node and peritoneum were metastasized in 9, 9, 11 and 5 patients, respectively. The KRAS gene was wild in 11, mutated in 7 and unknown in 8 patients. Bevacizumab with S-1 was used in 17 patients and bevacizumab with 5FU/LV was used in 9. Response and disease control rates were 50 and 100%, respectively. The median duration of progression-free survival was 9.1 months and the median time to treatment failure was 9.0 months. The incidences of all grades of neutropenia and hypertension were 31%, those of grade 3 or severer were 12%, and those of other adverse events were low. Grade 3 cerebral hemorrhage, grade 4 pulmonary embolism and grade 5 febrile neutropenia each occurred in 1 patient. CONCLUSION: The first-line chemotherapy combined bevacizumab with fluoropyrimidine for frail patients with unresectable or metastatic colorectal cancer in Japan was comparable to the safety and efficacy of combination therapy reported previously in Western countries.

[A resected case of effective treatment with S-1+CPT-11 combination chemotherapy for advanced gastric cancer].

We report a resected case of effective treatment with S-1+CPT-11 combination chemotherapy for advanced gastric cancer. The patient was a 65-year-old man who had a type 3 gastric cancer from the middle body of the stomach to the angle. An abdominal CT scan demonstrated bulky lymph node metastasis (cType 3, T3, N2, M0, cStage IIIb), which was then treated with S-1+CPT-11 (S-1 80 mg/m2 day 1-21, CPT-11 80 mg/m2 day 1, 15/5 weeksx2 courses)as neoadjuvant chemotherapy. After 2 courses of chemotherapy, the primary lesion and regional metastatic lymph nodes were reduced by CT (cType 3, T2, N2, M0, cStage IIIa). Total gastrectomy with D3 nodal dissection was performed. The histological diagnosis was pT2 (ss), pN0, sH0, pCY0, sP0, sM0, tub2, INF beta, ly0, v1, n0, stage I b, Cur A, and the histological effect of the main tumor was judged to be Grade 1b. He was treated by S-1 after surgery. The patient has been in good health without a recurrence for 3 years after surgery. This case suggests that neoadjuvant chemotherapy with S-1+CPT-11 is a potential regimen for advanced gastric cancer.

Epidermal growth factor receptor is a possible predictor of sensitivity to chemoradiotherapy in the primary lesion of esophageal squamous cell carcinoma.

BACKGROUND: Chemoradiotherapy (CRT) is currently performed for patients with esophageal squamous cell carcinoma (SCC). Some reports have revealed that patients who responded well to CRT had favorable outcomes, whereas poor responders conversely showed a worse prognosis. The aim of this study was to identify molecular markers predicting sensitivity to CRT. METHODS: We reviewed 62 patients with T(3-4), N-any, and M-any esophageal SCC treated with definitive CRT. The regimen comprised protracted 5-fluorouracil infusion and a 2-h infusion of cisplatinum combined with radiation therapy (2 Gy/day) at a total radiation dose of 60 Gy. The expressions of epidermal growth factor receptor (EGFR), vascular endothelial growth factor, cyclin D1, and proliferating cell nuclear antigen were investigated immunohistochemically in biopsy specimens obtained before treatment from all 62 patients. The immunoreactivities were compared with responsiveness to CRT, as evaluated by endoscopy. RESULTS: The complete response rate of the primary tumor estimated by endoscopy was 62% (13/21) in patients in the EGFR-positive group. The difference in the CR rate between EGFR-positive and -negative groups was significant (p = 0.037). The immunoreactivities of the other molecular markers did not show a significant correlation with the responsiveness of the primary lesion to CRT. Multiple logistic regression analysis revealed that positive immunostaining for EGFR was significantly correlated with primary CR for CRT in esophageal SCC. CONCLUSION: Among 62 patients with esophageal SCC, differences in the responsiveness of primary lesions to CRT were correlated with EGFR immunoreactivity assessed in the biopsy specimens. These results suggest that EGFR may help to predict the response of primary sites to definitive CRT in esophageal SCC, although the results should be confirmed in a larger, more homogeneous series.

Evaluation of prognostic factors of esophageal squamous cell carcinoma (stage II-III) after concurrent chemoradiotherapy using biopsy specimens.

BACKGROUND: Recently, attention has been directed to concurrent chemoradiotherapy (CRT) for the treatment of squamous cell carcinoma of the esophagus with regard to efficacy, quality of life and functional preservation, and survival periods comparable to those after standard surgical therapy have been reported in responders to CRT. However, there are some non-responders to CRT, and the prediction of the outcome after CRT is an important subject for future studies. In this study, using biopsy specimens obtained before CRT, we evaluated the relationships between biological markers and the outcome after CRT in order to determine the prognostic factors of CRT. METHODS: The subjects were 51 patients (42 males and nine females: median age 68 years). who were histologically confirmed to have squamous cell carcinoma of the esophagus at stage II or III (UICC). Concurrent CRT consisting of chemotherapy using 5FU and CDDP and radiation therapy (60 Gy) was performed as the initial treatment, and the relationships of overexpression of EGFR, p53, VEGF, PCNA and CyclinD1 were examined immunohistochemically in biopsy specimens collected before treatment. Overall survival was estimated by multivariate analysis. RESULTS: The percentages of patients overexpressing p53, VEGF, PCNA, CyclinD1, and EGFR were 33, 31, 37, 31 and 29%, respectively. On multivariate analysis, T stage (P = 0.0393) and PCNA (P = 0.0302) were found to be significant prognostic factors. CONCLUSIONS: PCNA overexpression appears to be a prognostic factor for squamous cell carcinoma of the esophagus after CRT.

Thymidylate synthase gene expression in primary tumors predicts activity of s-1-based chemotherapy for advanced gastric cancer.

PURPOSE: To evaluate the association between dihydropyrimidine dehydrogenase (DPD) and thymidylate synthase (TS) levels in primary gastric tumors and clinical response to S-1 or S-1 plus irinotecan in patients with unresectable advanced gastric cancer, and to investigate the molecular mechanism of augmented antitumor activity of the combination using human gastric cancer xenografts with high TS activity. MATERIALS AND METHODS: TS mRNA expression and DPD mRNA expression were measured by reverse transcription polymerase chain reaction in initial primary cancer biopsy specimens in 29 patients with advanced gastric cancer who had received S-1 alone (n=18) or in combination with irinotecan (n=11). In an experimental study, antitumor effects of S-1, irinotecan, and the combination were assessed in mice bearing human gastric tumors with high TS expression (4-1-ST and AZ-521 tumors) and low TS expression (SC-2 tumors), and activities of 5-fluorouracil-metabolizing enzymes were measured. RESULTS: In the clinical study, a strong statistical association between high TS expression and clinical resistance to S-1 alone was found (P = .009). In the experimental studies, S-1 plus irinotecan showed augmented antitumor activity against tumors with high TS activity (P < .01) compared with either agent alone. A potential mechanism for this effect was suggested by the significant reduction in TS activity observed following irinotecan administration in tumors with high TS activity. CONCLUSION: This study suggests that, via down-regulation of TS by irinotecan treatment, combination chemotherapy with S-1 and irinotecan could be effective in gastric cancer patients with high TS levels.

[S-1 combined with weekly paclitaxel in patients with advanced gastric cancer].

S-1 Combined with Weekly Paclitaxel in Patients with Advanced Gastric Cancer: Masahiro Gotoh, Shin-ichiro Kawabe and Hiroya Takiuchi (Dept. of Gastroenterology, Osaka Medical College) Summary Both paclitaxel and S-1 have been identified as an effective agent for the treatment of gastric cancer. Furthermore, weekly paclitaxel was found to have a better toxicity profile and to be as effective as an equivalently dosed conventional schedule of delivery every 3 weeks. Osaka Gastrointestinal Cancer Chemotherapy Study Group (OGSG) conducted the phase I/II study of weekly paclitaxel combined with S-1. S-1 was given orally at a fixed dosage of 40 mg/m2 bid for 14 consecutive days, followed by a week rest. Paclitaxel was scheduled to be given intravenously on days 1 and 8. The MTD of paclitaxel was presumed to be 60 mg/m2 because 50.0% of patients (2/4) developed DLTs (mainly grade 3 anorexia). Therefore, the RD of paclitaxel was estimated to be 50 mg/m2. This combination treatment was demonstrated to exhibit a tolerable toxicity profile with a high antitumor activity of 48% (14/29) and MST of 417 days. This regimen is investigated in a randomized phase II trial and may yet become a test arm in future phase III trials.

[Weekly administration regimen of paclitaxel (PTX) in patient with inoperable or recurrent gastric cancer].

Paclitaxel is one of the new drugs against advanced/recurrent gastric cancer. We report its efficacy and toxicity with weekly administration for advanced/recurrent gastric cancer. We administered 26 patients (postoperative/non-operation=9/17) PTX 80 mg/m(2)by 1-hour intravenous infusion once a week for 3 weeks followed by one week rest. Median PTX administrations were 2.0 cycles (range:1-22). Characteristics of the patients were median age of 62 (range: 37-78) and PS 0/1/2:2/17/7, male/female:18/8. Over grade 3 toxicities did not occur. The overall response rate was 14.3%, and the non-PD rate was 66.8%. Median time to treatment failure was 61 days and median survival time was 221 days. These results suggest that weekly PTX has modest activity with a favorable toxicity profile in patients with advanced/recurrent gastric cancer, and so this regimen may thus might be recommended in an outpatient treatment setting.

[A case of gastric cancer with multiple liver metastases resistant to TS-1 responding to chemotherapy with paclitaxel plus doxifluridine].

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

[Principles of managing chemotherapy-induced nausea and vomiting].

Chemotherapy-induced nausea and vomiting (emesis) can significantly affect a patient's quality of life, leading to poor compliance with further chemotherapy treatment. For patients treated with emetogenic chemotherapy, it is very important to prevent nausea and vomiting completely. The incidence and severity of nausea and/or vomiting in patients receiving chemotherapy are affected by numerous factors, including: 1) the specific chemotherapeutic agents used; 2) their dosage; 3) the schedule and route of administration; and 4) individual patient variability. Approximately 70 to 80% of all cancer patients receiving chemotherapy experience emesis, whereas 10% to 44% experience anticipatory emesis. The following general principles are recommended. 1) A 5-HT3 receptor antagonist should be administered prior to each day's 1st dose of moderately or highly emetogenic chemotherapy. 2) Dexamethasone should be administered once daily either orally or intravenously for every day of moderately or highly-emetogenic chemotherapy and for 2-3 days after chemotherapy for regimens that are likely to cause significant delayed-emesis. 3) The most effective way to treat anticipatory nausea and/or vomiting is to prevent it by using optimal antiemetic therapy during every cycle of treatment.

[Second-line chemotherapy in gastric cancer].

Japan Clinical Oncology Group (JCOG) conducted a randomized phase III trial that compared 5-FU alone with 5-FU+cisplatin (JCOG 9205). The primary endpoint of this study was overall survival, and both regimens showed equivalence not only in median survival time (approximately 7 months) but also in one- and two-year survival rate (28% vs 29%, and 7% vs 7%, respectively). The toxicities were significantly lower with 5-FU alone than with 5-FU+cisplatin. Then the JCOG steering committee determined that 5-FU alone should be the reference arm and overall survival should still be the primary endpoint in the next study (JCOG 9912). According to the monitoring report of this study at the interim analysis, median survival time of all patients registered for the study exceeded 11 months. Surprisingly, there was an improvement in median survival time from 7 months in JCOG 9205 to 11 months in JCOG 9912. Many newer agents were used, such as TS-1, CPT-11, docetaxel, and paclitaxel, which were absent during the previous study (JCOG 9205). Using these agents as a second-line treatment may cause the improvement of survival. Two phase II studies of CPT-11- and paclitaxel-based regimens indicate that patients derive benefit from second-line treatment, and this warrants further investigation in a randomized trial.

[A case of advanced gastric cancer with DIC treated by sequential MTX and 5-FU].

A 75-year-old man was admitted to our hospital complaining of gastric fatigue. Endoscope and CT scan revealed type 3 gastric cancer with paraaortic lymph nodal metastasis. Histological examination of the endoscopic biopsy revealed poorly differentiated adenocarcinoma. A blood examination and bone marrow biopsy revealed DIC causing bone marrow carcinosis. Chemotherapy with sequential therapy consisting of MTX and 5-FU was performed. Stretch of the fold and flatness of the ulcer were obtained against the gastric primary lesion observed endoscopically. Complete response was obtained against the lymph node around the abdominal aorta. Reduction of low back pain and DIC were observed. He was thus able to be discharged and sequential therapy was performed again over 2 months in outpatient care.

Adenovirus-mediated mda-7 gene expression radiosensitizes non-small cell lung cancer cells via TP53-independent mechanisms.

We examined the ability of adenoviral-mediated expression of the melanoma differentiation associated gene-7 (Ad-mda-7), to radiosensitize non-small cell lung cancer (NSCLC) cell lines (A549 (wt-TP53/wt-RB1) and H1299 (del-TP53/wt-RB1)), and normal human lung fibroblast (NHLF) lines (CCD-16 and MRC-9). Results of clonogenic assays indicated that Ad-mda7 enhanced the radiosensitivity of the NSCLC cells independent of their TP53 gene status. On the other hand, the NHLF cell lines seemed to be relatively resistant to the cytotoxic effects of Ad-mda7 and were not radiosensitized compared with the NSCLC cells. We further examined the basis for this difference in the ability of Ad-mda7 to radiosensitize NSCLC cells compared with normal cells. Radiation-induced apoptosis was restored in the NSCLC lines, but not in the normal lines. Western blot analysis revealed that Ad-mda7 enhances radiosensitivity independently of any ability to upregulate the expression of Fas or Bax in NSCLC cells. Further analysis indicated that phosphorylated c-Jun expression was increased by Ad-mda7 in both A549 and H1299 cells, but not in CCD-16 cells. These results support the use of gene replacement with Ad-mda7 in combination with radiotherapy for the treatment of NSCLC.

Enhancement of radiotherapy by oleandrin is a caspase-3 dependent process.

Cardiac glycosides such as digitoxin and ouabain have previously been shown to be selectively cytotoxic to tumor as opposed to normal cells. Moreover, this class of agents has also been shown to act as potent radiosensitizers. In the present study we explored the relative radiosensitization potential of oleandrin, a cardiac glycoside contained within the plant extract known as Anvirzel that recently underwent a Phase I trial as a novel drug for anticancer therapy. The data show that oleandrin produces an enhancement of sensitivity of PC-3 human prostate cells to radiation; at a cell survival of 0.1, the enhancement factor was 1.32. The magnitude of radiosensitization depended on duration of exposure of cells to drug prior to radiation treatment. While a radiosensitizing effect of oleandrin was evident with only 1h of cell exposure to drug, the effect greatly increased with 24h oleandrin pretreatment. Susceptibility of PC-3 cells to oleandrin and radiation-induced apoptosis was dependent on activation of caspase-3. Activation was greatest when cells were exposed simultaneously to oleandrin and radiation. Inhibition of caspase-3 activation with Z-DEVD-FMK abrogated the oleandrin-induced enhancement of radiation response suggesting that both oleandrin and radiation share a caspase-3 dependent mechanism of apoptosis in the PC-3 cell line.

Inhibition of human lung cancer growth following adenovirus-mediated mda-7 gene expression in vivo.

Overexpression of the melanoma differentiation associated gene-7 (mda-7) in vitro results in suppression of lung cancer cell proliferation. However, the ability of MDA-7 to suppress lung cancer in vivo has not been previously demonstrated. In this study, we investigated the possibility of inducing overexpression of the mda-7 gene in human non-small cell lung carcinoma cells in vivo and its effects on tumor growth. Adenovirus-mediated overexpression of MDA-7 in p53-wild-type A549 and p53-null H1299 subcutaneous tumors resulted in significant tumor growth inhibition through induction of apoptosis. In addition, decreased CD31/PECAM expression and upregulation of APO2/TRAIL were observed in tumors expressing MDA-7. In vivo studies correlated well with in vitro inhibition of lung tumor cell proliferation and endothelial cell differentiation mediated by Ad-mda7. These data demonstrate that Ad-mda7 functions as a multi-modality anti-cancer agent, possessing both, pro-apoptotic and anti-angiogenic properties. We demonstrate for the first time the potential therapeutic effects of Ad-mda7 in human lung cancer.

[Effectiveness of chemotherapy for outpatients with gastric or colorectal cancer].

We retrospectively evaluated the efficacy of chemotherapy regarding symptom control, toxicity and discharge rate in 39 patients with gastric or colorectal cancer. Treatment consisted of TS-1 (n = 16), TS-1 + CPT-11 (n = 8), CDDP + CPT-11 (n = 5), paclitaxel (n = 8) and MTX + 5-FU (n = 4) for gastric cancer and 5-FU + l-leucovirin (n = 6), 5-FU + CPT-11 (n = 5), MMC + CPT-11 (n = 8) and 5-FU protracted continuous infusion (n = 5) for colorectal cancer. The rates of symptom improvement were the following: pain 60% (10/15), general fatigue 56% (5/9) and abdominal fullness 53% (8/15). 87% (34/39) of the patients were discharged from hospital and continued chemotherapy as outpatients grade 3 toxicities were the following: anemia 10.3%, nausea and/or vomiting 7.7%, diarrhea 5.1%. There was no treatment related death. The rates of outpatient based treatment duration improvement were the following: gastric cancer: 47.6%, colorectal cancer: 72%. These data suggest that these treatments for gastric and colorectal cancer are safe and improve the patients' QOL.