Eunmi Nam

Salvage Chemotherapy for Pretreated Gastric Cancer: A Randomized Phase III Trial Comparing Chemotherapy Plus Best Supportive Care With Best Supportive Care Alone

PURPOSE When designing this trial, there was no evidence that salvage chemotherapy (SLC) in advanced gastric cancer (AGC) resulted in substantial prolongation of survival when compared with best supportive care (BSC). However, SLC is often offered to pretreated patients with AGC for anecdotal reasons. PATIENTS AND METHODS Patients with AGC with one or two prior chemotherapy regimens involving both fluoropyrimidines and platinum and with an Eastern Cooperative Oncology Group performance status (PS) 0 or 1 were randomly assigned in a ratio of 2:1 to SLC plus BSC or BSC alone. Choice of SLC-either docetaxel 60 mg/m(2) every 3 weeks or irinotecan 150 mg/m(2) every 2 weeks-was left to the discretion of investigators. Primary end point was overall survival (OS). RESULTS Median OS was 5.3 months among 133 patients in the SLC arm and 3.8 months among 69 patients in the BSC arm (hazard ratio, 0.657; 95% CI, 0.485 to 0.891; one-sided P = .007). OS benefit for SLC was consistent in most of the prospectively defined subgroups, including age, PS, number of prior treatments, metastatic sites, hemoglobin levels, and response to prior chemotherapy. SLC was generally well tolerated, and adverse events were similar in the SLC and BSC arms. We found no median OS difference between docetaxel and irinotecan (5.2 v 6.5 months; P = .116). CONCLUSION To our knowledge, this is the largest phase III trial comparing SLC plus BSC with BSC alone in AGC. In pretreated patients, SLC is tolerated and significantly improves OS when added to BSC.

Early Imatinib Mesylate-Induced Hepatotoxicity in Chronic Myelogenous Leukaemia

Imatinib mesylate is the first molecule of targeted therapy in chronic myelogenous leukaemia inhibiting constitutively activated BCR-ABL kinase. There are no long-term follow-up studies of large sample sizes to assess the toxicity of the use of imatinib mesylate over 10 years. Several cases of hepatotoxicity, including fatal liver failure, have been associated with the long-term use of imatinib mesylate. We report here on a patient who experienced immediate dominant cholestatic damage of the liver and mild hepatocyte damage during imatinib mesylate therapy. This differs from most reports showing dominantly acute hepatitis with necrosis associated with the use of imatinib mesylate.

A Randomized Double-Blind Placebo-Controlled Study of Low-Dose Intravenous Lorazepam to Reduce Procedural Pain During Bone Marrow Aspiration and Biopsy

OBJECTIVE To evaluate the efficacy of intravenous lorazepam as premedication for bone marrow aspiration and biopsy (BMAB). DESIGN Randomized, double-blind, placebo-controlled. PATIENTS One hundred and thirty-eight consenting patients planned to receive BMAB. INTERVENTION Patients were randomly assigned to receive either intravenous lorazepam 1 mg or placebo just prior to BMAB. SETTING Tertiary referral center, inpatient setting. OUTCOME MEASURES A questionnaire was used to determine the patient perception about the procedure and pain at baseline, which was completed just after the procedure, and the next day after the BMAB. Pain was rated using a 10-cm linear visual analog scale (VAS). RESULTS The mean VAS scores measured during the BMAB examination were 6.0 for lorazepam vs 6.2 for placebo. Few adverse events were noted during intravenous lorazepam administration. The patients in the lorazepam group were more likely to accept the next BMAB (P = 0.044). CONCLUSION Intravenous lorazepam was safe in patients undergoing BMAB and was more effective than placebo in enhancing cooperation during BMAB and willingness to undergo another procedure. However, use of lorazepam 1 mg provided no reduction in the pain associated with BMAB. Further studies should focus on providing appropriate analgesia for this potentially painful procedure.

Malignant Gastrointestinal Stromal Tumor in a Patient with Neurofibromatosis type 1

Neurofibromatosis type 1 (von Recklinghausens disease, NF-1) is an autosomal-dominant neurocutaneous disorder characterized by abnormal skin pigmentation (café au lait spots and axillary freckling), cutaneous and plexiform neurofibromas, skeletal dysplasias, and Lisch nodules (pigmented iris hamartomas). Gastrointestinal stromal tumors (GISTs) are the most common tumors of mesenchymal origin in the gastrointestinal tract, mesentery, omentum, and retroperitoneum. Here, we report a case of GIST in the ileum of a 76-year-old woman previously diagnosed as NF-1. She was admitted due to sudden onset of abdominal pain. Contrast enhanced CT scan revealed a moderately defined, peripherally enhanced soft tissue mass of about 8.8×7.3cm, originating from the small bowel in the left of the abdomen. Surgical excision was performed and the tumor was found to be composed of tumor cells that were positive for c-kit protein. The patient started imatinib treatment a month later, but stopped medication due to dyspepsia after a few months and eventually progressed after 18 months

Oxaliplatin and UFT combination chemotherapy in patients with metastatic colorectal cancer.

A phase II study was performed to evaluate the clinical efficacy and toxicity of oxaliplatin combined with uracil and tegafur (UFT) in patients with advanced colorectal cancer previously treated with a fluoropyrimidine-based regimen. From January to December 1999, 34 patients were enrolled in this study. Patients received intravenous oxaliplatin 130 mg/m2 on day 1 and daily oral UFT 350 mg/m2 in 3 divided doses for 21 days and repeated every 21 days. Thirty-one of 34 patients were assessable for response and 32 patients for toxicity. Partial response was observed in four patients and stable disease in six patients. The response rate was 12.9% (95% CI, 3.6–29.8%) and median duration of response was 17 weeks. The median overall survival and progression-free survival of all patients were 26 weeks (range, 3–90+ weeks) and 9 weeks (range, 3–56 weeks), respectively. Sensory neuropathy was the most common toxicity, but there was no severe toxicity (>grade II) except for a case of grade III neutropenia. We conclude that oxaliplatin and UFT combination chemotherapy was well tolerated without significant toxicities. The results of this trial will serve as the basis for designing new clinical trials with a different dose or schedule.

Intestinal marginal zone B-cell lymphoma of MALT type: clinical manifestation and outcome of a rare disease

Intestinal marginal zone B‐cell lymphoma of the MALT type (I‐MZL) is a relatively uncommon form of lymphoma. Twenty‐seven patients with histologically‐confirmed I‐MZL were analyzed. The patients initially presented with abdominal pain (62.9%), and diarrhea (22.2%). The most common involved site was the ileo‐caecal area (40.7%). Musshoff’s stage IE, IIE1, IIE2, IIIE and IV were present in 44%, 15%, 11%, 7.4% and 22% respectively. Sixty‐three percent were in the low‐risk group according to the Follicular Lymphoma International Prognostic Index. Complete response and partial response were achieved in 82% and 4% patients. The estimated 5‐year overall survival (OS) and progression‐free survival (PFS) rates were 86% and 54%. Stage ≥ IIE2 was determined to be a poor prognostic factor for PFS and OS. I‐MZL commonly manifests in an early‐stage, low‐risk state and tends to respond well to local and systemic treatment with favorable prognosis. I‐MZL tends to be an indolent disease – characterized by prolonged survival with frequent relapses, similarly to other site MZLs.

Expression of Cyclooxygenase-2 in Human Breast Cancer: Relationship with HER-2/neu and other Clinicopathological Prognostic Factors

PURPOSE Previous epidemiologic studies have demonstrated that nonsteroidal anti-inflammatory drugs can reduce the risk of breast cancer, and this possibly happens via cyclooxygenase (COX) inhibition. Moreover, growth factor-inducible COX-2, which is overexpressed in neoplastic tissue, is an attractive therapeutic target. Thus, we evaluated the expression of COX-2 in breast cancer tissues, and we assessed the association between COX-2 expression and HER-2/neu expression and also with several clinicopathological features. MATERIALS AND METHODS We analyzed the surgical specimens from 112 women with breast cancer who had undergone lumpectomy or mastectomy. The expressions of COX-2, HER-2/neu, MMP-2 and TIMP-2 were determined immunohistochemically. The correlations between COX-2 expression and several variables, including clinicopathological factors, HER-2/neu expression, MMP-2 expression and TIMP-2 expression were analyzed. Survival analysis was also performed with respect to COX-2 overexpression. RESULTS The overexpression of COX-2 protein was observed in 28.6% of the breast cancer tissues. Tumors with lymph node metastasis more frequently showed COX-2 overexpression than did those tumors without metastasis (p=0.039), and the increased COX-2 expression correlated positively with HER-2/neu overexpression (p=0.000). No significant differences were found for the MMP-2 or TIMP-2 expression rates in the COX-2 positive and negative groups. The survival analysis revealed no significant differences according to the COX-2 expression. CONCLUSION This study results suggest that increased COX-2 expression is related with the progression of breast cancer, e.g., with lymph node invasion. COX-2 overexpression found to be related with HER-2/neu overexpression, but not with MMP-2 or TIMP-2 expression. These results support the potential use of selective agents that inhibit COX-2 or HER-2/neu for the management of breast cancer.

Thalidomide for Treating Metastatic Hepatocellular Carcinoma: A Pilot Study

Background Thalidomide has been reported to have antitumor activity for treating metastatic hepatocellular carcinoma (HCC). We evaluated the safety and efficacy of using thalidomide for treating selected patients with unresectable or metastatic HCC, and their disease was refractory to systemic chemotherapy. Methods Eight patients with measurable and metastatic HCC that had progressed with prior systemic chemotherapy and who desired further active therapy were enrolled in this study. Thalidomide was given orally at bedtime and it was started at 200 mg/day with no further dose escalation. The response was measured at 2-month intervals. Results The median age was 44 years (range: 34-52 years) and all the patients had received doxorubicin-based systemic chemotherapy prior to their enrollment. Each patient received thalidomide for a median of 152 days (range: 5-422 days). One partial response was observed (12.5%, 95% CI; 0-42%) along with 4 cases of stable diseases. The most commonly encountered toxicity was somnolence; grade 3 somnolence was noted for one patient, which led to treatment discontinuation. Skin rash was observed in one responding patient. Conclusions The results indicate that thalidomide may feasibly offer disease stabilization to metastatic HCC patients. Further dose escalation of thalidomide, or its combination with other chemotherapeutic agents, may be of interest and this should be investigated for treating patients with metastatic HCC.

A Pilot Study of Cisplatin, Irinotecan, Leucovorin and 5-fluorouracil (PILF) Combination Chemotherapy for Advanced Gastric Cancer

PURPOSE Irinotecan, in combination with leucovorin/5-fluorouracil (FU) or with cisplatin, is known to be active for treating advanced gastric cancer (AGC). This pilot study evaluated a novel three-drug combination of irinotecan, leucovorin/FU and cisplatin as a first-line treatment of AGC. The primary endpoint was to assess the feasibility in anticipation of conducting a larger phase II study. MATERIALS AND METHODS Chemotherapy-naive AGC patients received irinotecan 150 mg/m(2) on day 1, and leucovorin 200 mg/m(2) and a 22-h infusion of FU 1000 mg/m(2) on days 1 and 2. Cisplatin 30 mg/m(2) was administered on day 2. Treatment was repeated every 2 weeks until disease progression or unacceptable toxicity. RESULTS Of the 17 eligible patients, two patients had an ECOG performance status of 2 and their median age was 48 years (range: 31 to 69). A total of 117 chemotherapy cycles were delivered (median: 6, range: 1 to 12). The causes of treatment discontinuation were disease progression in 9 patients (53%), refusal (35%) and toxicity (12%). Although grade 3 or 4 neutropenia (41% of patients) was the major toxicity that required dose adjustments, only one episode of febrile neutropenia occurred. Grade 3 or 4 nausea and vomiting, diarrhea and fatigue were observed in 35%, 35% and 29% of patients, respectively. None of the patients died of toxicity during treatment. Of the 16 patients who were evaluable for response, 7 (44%) experienced a partial response. CONCLUSION This novel multi-drug combination was tolerated well in patients with AGC. Based on the encouraging efficacy and tolerability, a randomized phase II study is ongoing in this disease setting.

Expression of cyclooxygenase-2 in Korean breast cancer patients and the in vitro growth inhibitory effect of celecoxib in breast cancer cells

9715 Background: Epidemiologic studies indicated that nonsteroidal antiinflammatory drugs can reduce the risk of breast cancer, possibly via cyclooxygenase(COX) inhibition. The growth factor-inducible COX-2, which is overexpressed in neoplastic tissue, is attractive target of cancer treatment. METHODS We evaluated the relationships between COX-2 overexpression, Her-2/neu overexpression, and clinicopathological features in 112 Korean breast cancer patients. Protein expression was analysed by immunohistochemical stain in paraffin embedded tissues using monoclonal antibody for COX-2 and Her-2/neu. To explore the role of selective COX-2 inhibitor, celecoxib, and humanized anti-Her-2/neu monoclonal antibody trastuzumab in vitro, MTT assay of the breast cancer cells which have different expression levels of the COX-2 and Her-2/neu protein (MCF 7, COX-2 -, Her-2/neu -; MCF 7/H18, COX-2 -, Her-2/neu +; SKBR-3, COX-2 weak +, Her-2/neu +) were studied and a cell cycle analysis was performed. RESULTS Increased COX-2 expression was observed in 78.6% of breast cancer tissues. Increased COX-2 expression correlated positively with lymph node metastasis (p=0.001) and Her-2/neu overexpression (p=0.001). Celecoxib induced a G1 arrest and reduced cell survival independent of whether or not the cells expressed COX-2. Apoptosis was increased in the tumor cells in response to celecoxib. Celecoxib and trastuzumab showed additive effect in growth inhibition of Her-2/neu overexpressed SKBR-3. CONCLUSIONS Taken together, COX-2 overexpression occurs frequently in breast cancer patients and increased COX-2 expression is related with cancer progression. Furthermore, in vitro data indicate that the growth inhibitory effects of celecoxib probably are mediated through COX-2 independent mechanisms. Our results open up the possibility to consider COX-2 as an therapeutic target in breast cancer. No significant financial relationships to disclose.