Phase II trial of S-1 monotherapy in elderly or frail patients with metastatic colorectal cancer.

A phase II study was conducted to evaluate S-1 monotherapy in previously untreated elderly or frail metastatic colorectal cancer patients. A total of 48 elderly (70-85 years old) and frail [Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2 and 65-69 years old] patients were eligible for first-line S-1 of 35 mg/m(2) given twice daily for 2 weeks followed by 1 week of rest. The overall response rate (ORR) for all patients was 19%. Similarly, the ORR for frail and elderly patients was 22% and 18%, respectively. Median progression-free survival (PFS) and overall survival (OS) for all patients were 3.9 months (95% CI, 3.0-4.8) and 11.3 months (95% CI, 7.4-15.2), respectively. For frail patients, PFS was 1.4 (95% CI, 0.8-2.0) vs. 4.3 months (95% CI, 3.0-5.4) for the elderly (P = 0.016). OS was significantly longer for elderly patients than for frail patients (13.1 months, 95% CI, 9.5-16.7) vs. (4.1 months, 95% CI, 3.2-5.0; P = 0.01). Toxicity was mild to moderate, as only 29% of patients experienced grade 3 toxicity. Grade 4 toxicity and febrile neutropenia did not occur; however, two frail patients died from grade 5 treatment-related infections. Generally, S-1 monotherapy was well-tolerated and efficacious in the elderly patient group, but not in the frail patient group. Considering performance status and co-morbidities in patients >70 years old, S-1 monotherapy may be a first-line therapeutic option for elderly mCRC patients.

In vitro pharmacogenomic database and chemosensitivity predictive genes in gastric cancer.

Gastric cancer is one of the most common cancers worldwide, and there are clinical caveats in predicting tumor response to chemotherapy. This study describes the construction of an in vitro pharmacogenomic database, and the selection of genes associated with chemosensitivity in gastric cancer cell lines. Gene expression and chemosensitivity databases were integrated using the Pearson correlation coefficient to give the GC-matrix. The 85 genes were selected that were commonly associated with chemosensitivity of the major anticancer drugs. We then focused on the genes that were highly correlated with each specific drug. Classification of cell lines based on the set of genes associated with each drug was consistent with the division into resistant or sensitive groups according to the chemosensitivity results. The GC-matrix of the gastric cancer cell line database was used to identify different sets of chemosensitivity-related genes for specific drugs or multiple drugs.

Pleural epithelioid hemangioendothelioma.

Epithelioid hemangioendothelioma (EHE) is a rare tumor of vascular origin. While it can be found in any tissue, it is most often found in lung and liver and usually has an intermediate behavior. EHEs originating from pleural tissue have been less frequently described than those from other sites. Furthermore, to date, all of the cited pleural EHEs were described as highly aggressive. In the present report, we describe a rare case of pleural EHE extending to lung and bone in a 31-year-old woman. The histological diagnosis was confirmed by both conventional examination and immunohistochemistry. Her disease stabilized during the 4th course of adriamycin (45 mg/m(2), day 1-3), dacarbazine (300 mg/m(2), day 1-3) and ifosfamide (2,500 mg/m(2), day 1-3) with mesna, and she survived for 10 months after the diagnosis.

A case of successful intrapleural chemotherapy with Cisplatin plus cytarabine for intractable malignant pleural effusion.

When conventional treatments of malignant pleural effusion, such as repeated thoracentesis, closed thoracotomy and pleurodesis by instilled sclerosing agents, are ineffective, there are few alternative therapies available. Our case involves a 47-year-old woman with uterine cervical carcinoma suffering from malignant pleural effusion. She presented with a chief complaint of severe dyspnea, and was classified as an Eastern Cooperative Oncology Group (ECOG) performance status of 4. Her underlying cervical carcinoma progressed despite various systemic chemotherapy regimens. In addition, pleural effusion persisted in spite of 4 weeks of drainage through the thoracotomy tube and talc pleurodesis. Under such circumstances, we attempted intrapleural chemotherapy with cisplatin plus cytarabine, which resulted in significant decrease of the pleural effusion. No serious systemic toxicities, including myelosuppression, were observed. As a result, the patient's dyspnea was relieved, and her ECOG performance status improved from 4 to 2. However, the thoracotomy tube was not removed due to subsequent iatrogenic pneumothorax. Pleural effusion did not recur for the 4 weeks leading up to her death.

An Open-Label, Randomized, Parallel, Phase III Trial Evaluating the Efficacy and Safety of Polymeric Micelle-Formulated Paclitaxel Compared to Conventional Cremophor EL-Based Paclitaxel for Recurrent or Metastatic HER2-Negative Breast Cancer.

PURPOSE: Genexol-PM is a Cremophor EL-free formulation of low-molecular-weight, non-toxic, and biodegradable polymeric micelle-bound paclitaxel. We conducted a phase III study comparing the clinical efficacy and toxicity of Genexol-PM with conventional paclitaxel (Genexol). MATERIALS AND METHODS: Patients were randomly assigned (1:1) to receive Genexol-PM 260 mg/m2 or Genexol 175 mg/m2 intravenously every 3 weeks. The primary outcome was the objective response rate (ORR). RESULTS: The study enrolled 212 patients, of whom 105 were allocated to receive Genexol-PM. The mean received dose intensity of Genexol-PM was 246.8±21.3 mg/m2 (95.0%), and that of Genexol was 168.3±10.6 mg/m2 (96.2%). After a median follow-up of 24.5 months (range, 0.0 to 48.7 months), the ORR of Genexol-PM was 39.1% (95% confidence interval [CI], 31.2 to 46.9) and the ORR of Genexol was 24.3% (95% CI, 17.5 to 31.1) (pnon-inferiority=0.021, psuperiority=0.016). The two groups did not differ significantly in overall survival (28.8 months for Genexol-PM vs. 23.8 months for Genexol; p=0.52) or progression-free survival (8.0 months for Genexol-PM vs. 6.7 months for Genexol; p=0.26). In both groups, the most common toxicities were neutropenia, with 68.6% occurrence in the Genexol-PM group versus 40.2% in the Genexol group (p < 0.01). The incidences of peripheral neuropathy of greater than grade 2 did not differ significantly between study treatments. CONCLUSION: Compared with standard paclitaxel, Genexol-PM demonstrated non-inferior and even superior clinical efficacy with a manageable safety profile in patients with metastatic breast cancer.

A case of paraneoplastic nephrotic syndrome in a patient with ovarian carcinoma.

Nephrotic syndrome is a rare manifestation of malignancy associated with paraneoplastic syndrome. Paraneoplastic nephrotic syndrome has been reported in various malignancies: malignant lymphoma, colon cancer, lung cancer and prostate cancer. However, an ovarian carcinoma associated with nephrotic syndrome has rarely been reported. Only six cases of ovarian carcinoma associated paraneoplastic nephrotic syndrome has been reported worldwide, but no cases have been reported in Korea. Here, we report a case of paraneoplastic nephrotic syndrome in a patient with an ovarian carcinoma. The patient presented with ascites, proteinuria and hypoalbuminemia. An initial computed tomography (CT) scan and ultrasonography evaluations showed no specific findings suggestive of an ovarian tumor. Despite treatment for nephrotic syndrome, the symptoms became more aggravated. There after, follow up evaluation at Yonsei University Medical Center, including serum CA 125, pelvis MRI and peritoneal fluid examination were performed. On the pelvis MRI, a left ovarian mass was detected with an ascitic fluid collection. The serum CA 125 level was elevated to 2211 U/ml. The peritoneal fluid cytological examination showed malignant cells suggestive of an ovarian carcinoma. Combination chemotherapies including paclitaxel plus carboplatin, topotecan plus gemcitabine and oxaliplatin plus capecitabine were administered to the patient, and complete remission was achieved on image and tumor marker studies. There was complete recovery from the nephrotic syndrome with no evidence of ascites and proteinuria. These findings suggest that nephrotic syndrome caused by paraneoplastic syndrome can be resolved only after the complete control of the underlying malignancy.

Paclitaxel combined with ifosfamide in anthracycline- and docetaxel-pretreated metastatic breast cancer: activity independence of prior docetaxel resistance.

BACKGROUND: We evaluated the efficacy and tolerability of combined paclitaxel and ifosfamide in anthracycline- and docetaxel-pretreated metastatic breast cancer (MBC). METHODS: Patients received paclitaxel (175 mg/m(2) i.v. in a 3-h infusion) on day 1 and ifosfamide (1.5 g/m(2) i.v. in a 15-min infusion) on days 1-3, every 3 weeks for a maximum of nine cycles. The tumor response was assessed every two cycles. RESULTS: We enrolled 34 patients with a median age of 50 years. Thirty patients had visceral metastases. Anthracycline- and docetaxel-based chemotherapy had previously been administered to 18/13 and 13/21 patients, respectively, in (neo)adjuvant/metastatic settings. Three patients had not previously received anthracycline due to abnormal cardiac functions. A total of 174 cycles of chemotherapy were delivered with a median of six cycles. The response rate under the intent-to-treat analysis was 23.5% (all partial responses) with a median response duration of 14 months. The disease control rate was 70.6%. The median progression-free and overall survival were 5.9 and 8.5 months, respectively. There was no apparent relationship between activity and prior docetaxel resistance. The incidence of grade III/IV neutropenia was 46.6% (81 of 174 cycles) with febrile neutropenia of only 1.7%. Major grade III/IV non-hematological toxicities included peripheral neuropathy (6 of 34 patients) and infection (4 of 34 patients). There were no treatment-related deaths. CONCLUSION: Paclitaxel combined with ifosfamide was effective and tolerable in anthracycline-/docetaxel-pretreated MBC. Overcoming docetaxel resistance by using paclitaxel in combination with ifosfamide needs to be addressed through further investigation.

Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided versus empirical chemotherapy in unresectable non-small cell lung cancer.

BACKGROUND: We retrospectively compared adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided and empirical chemotherapies for unresectable non-small cell lung cancer (NSCLC) in this case-control study. PATIENTS AND METHODS: Unresectable NSCLC patients receiving ATP-CRA-guided platinum-based doublets as first-line therapy were enrolled as cases (n=27; 14 platinum-sensitive and 13 platinum-resistant patients). Performance status, stage, and chemotherapeutic regimen-matched patients receiving empirical chemotherapy were selected from the retrospective database as controls (n=93) in a case to control ratio of approximately 1:3. RESULTS: Response rate and survival (progression-free; overall) in both groups were not significantly different. However, the platinum-sensitive subgroup by ATP-CRA showed a higher response rate than the empirical group (71 versus 38%; p=0.023) with a trend toward longer progression-free survival (8.7 versus 4.8 months for platinum-sensitive versus empirical; p=0.223) and overall survival (not reached versus 12.6 months for platinum-sensitive versus empirical for p=0.134). CONCLUSION: ATP-CRA may be helpful in selecting platinum-responsive patients in unresectable NSCLC. We consider that nonplatinum doublets in platinum-resistant patients by ATP-CRA may be a more adapted approach than platinum-based doublets in future clinical trials.

Lemierre syndrome: a case of postanginal sepsis.

Lemierre syndrome is a rare disease that's characterized by internal jugular vein thrombosis and septic emboli. These symptoms typically develop after acute oropharyngeal infection by Fusobacterium necrophorum. Although this syndrome is less frequently seen in modern times due to the availability of antibiotics, physicians must be aware of the syndrome in order to initiate prompt antibiotics therapy, including coverage of the anerobic organisms. We discuss here the case of an 18-year-old female with Lemierre syndrome and we review the relevant literature on this syndrome.

Adenosine triphosphate-based chemotherapy response assay (ATP-CRA)-guided platinum-based 2-drug chemotherapy for unresectable nonsmall-cell lung cancer.

BACKGROUND: The study investigated correlations between adenosine triphosphate / chemotherapy response assay (ATP-CRA) and clinical outcomes after ATP-CRA-guided platinum-based chemotherapy for unresectable nonsmall-cell lung cancer (NSCLC). METHODS: The authors performed an in vitro chemosensitivity test, ATP-CRA, to evaluate the chemosensitivities of anticancer drugs such as cisplatin, carboplatin, paclitaxel, docetaxel, gemcitabine, and vinorelbine for chemonaive, unresectable NSCLC. The cell death rate was determined by measuring the intracellular ATP levels of drug-exposed cells compared with untreated controls. A sensitive drug was defined as a drug producing 30% or more reduction in ATP compared with untreated controls. Assay-guided platinum-based 2-drug chemotherapy was given to patients with pathologically confirmed NSCLC. RESULTS: Thirty-four patients were enrolled. Thirty tumor specimens were obtained by bronchoscopic biopsies and 4 obtained surgically. The median age was 61 years and 27 patients had an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. The response rate was 43.8%. At a median follow-up period of 16.9 months, the median progression-free and overall survivals were 3.6 and 11.2 months, respectively. Patients were dichotomized into the platinum-sensitive (S; 20 patients) and resistant (R; 14 patients) groups. The positive/negative predictive values were 61.1% and 78.6% with a predictive accuracy of 68.8%. Although without significant differences in pretreatment parameters, the S-group showed better clinical response (P=.036), longer progression-free survival (P=.060), and longer overall survival (P=.025). CONCLUSIONS: Despite using bronchoscopic biopsied specimens, ATP-CRA and clinical outcomes correlated well after assay-guided platinum-based 2-drug chemotherapy for unresectable NSCLC. There was a favorable response and survival in the platinum-sensitive vs resistant groups.

Infusional 5-Fluorouracil, Leucovorin and Docetaxel in Advanced Gastric Cancer.

PURPOSE: This study was performed to estimate the response rate and toxicity of a combination chemotherapy, which included infusional 5-Fluorouracil, Leucovorin and Docetaxel in the treatment of patients with an advanced gastric carcinoma. MATERIALS AND METHODS: Twenty two advanced gastric cancer patients, with a bidimensionally measurable or an evaluable disease, were enrolled in this study. The patients received a 5-fluorouracil 1, 000 mg/m2 intravenous (IV) 24 hour infusion (Day 1~3), leucovorin 20 mg/m2 (Day 1~3) and docetaxel 75 mg/m2 intravenously (Day 2) every 3 weeks. RESULTS: The overall response rate was 45.0%. The median duration of response was 10.0 weeks (range: 4~24), the median time to response was 8 weeks (range: 8~20) the median time to progression was 30.0 weeks (95% CI: 16.3~43.2) and the median overall survival duration was 36.0 weeks (95% CI: 1.7~70.2). The median cumulative dose of 5-fluorouracil were 316.2 mg/m2/week and docetaxel was 23.9 mg/m2/week. WHO grade III, IV neutropenia, thromocytopenia and anemia occurred in 50.0%, 4.5% and 4.5% of patients, respectively. There were no occurrence of WHO grade III and IV nausea, vomiting, mucositis, conspitation, diarrhea, or neurotoxicity. CONCLUSION: This chemotherapy regimen, including infusional 5-fluorouracil, leucovorin and docetaxel was an active agent against advanced gastric cancer patients, especially for previous chemotherapy naive patients.

Paclitaxel and Cisplatin Combination Chemotherapy in Pretreated Breast Cancer.

PURPOSE: A single institute trial of combination chemotherapy, with paclitaxel and cisplatin, in patients with metastatic breast cancer, having failed previous combination chemotherapy, was performed. MATERIALS AND METHODS: Patients were only eligible for this study if there disease had progressed, following treatment with previous chemotherapy, in either an adjuvant or a metastatic setting. Paclitaxel 175 mg/m2 was administered as a 3-hour continuous infusion on day 1, and cisplatin 80 mg/m2 was administered for 2 hours on day 2, with adequate hydration. This was repeated every 3 weeks, and continued until one of the following events occurred: disease progression, unacceptable adverse effect or treatment refusal by the patient. Intercurrent palliative radiotherapy, or concurrent hormonal therapy, was permitted, depending on each patient's status. All the endpoints were evaluated under the principle of intention to treat analysis. RESULTS: A total of 24 patients entered the study, and 18 had at least one measurable lesion, but 6 did not. The objective response rate of the 18 patients was 50%(9/18). Two were complete responses and seven showed partial responses. The median response duration, progression free and overall survival were 5.3 months (range, 4~18), 6 months (95% CI, 5~7) and 12 months (95% CI, 7~17), respectively. 67% of the planned dose was administered. Out of a total 135 cycles administered, about 20% of cycles showed grade 3 or 4 leukopenia and 7% showed grade 3 thrombocytopenia. Two patients suffered from pneumonia, and one experienced neutropenic fever. Mucositis, greater than grade 3, existed in three cases. No treatment related deaths were reported. CONCLUSION: The combination chemotherapy, with paclitaxel and cisplatin, was active in the treatment of metastatic breast cancer patients having failed previous chemotherapy.

Phase II Study of Gemcitabine and Vinorelbine as Second-Line Chemotherapy in Non-Small Cell Lung Cancer.

PURPOSE: With the increased use of chemotherapy for non small cell lung cancer (NSCLC), a growing group of patients can now be considered for second-line chemotherapy. However, guidelines for the second line treatment remain to be developed. The objective of this study was to evaluate the efficacy and safety of the gemcitabine and vinorelbine combination therapy in patients with advanced NSCLC, pretreated with taxane and platinum based regimens. Gemcitabine has already demonstrated activity in this patient group, with the combination therapy having been reported to be well tolerated in previous phase I/II studies. MATERIALS AND METHODS: Forty two patients with advanced NSCLC (stages III/IV), having received prior taxane and platinum based chemotherapy, with an ECOG performance status (PS) 0~2, and unimpaired hematopoietic and organ function, were treated with vinorelbine, 20 mg/m2, followed by gemcitabine, 1, 000 mg/m2, both administered on days 1, 8 and 15, every 4 weeks. RESULTS: Out of the 42 patients enrolled, 41 were evaluable for their response, and all 42 for their toxicity. The patient's characteristics were as follows; median age=60 years (42~73), median PS=1 (range 0~2), a gender ratio 31: 11 males/females, with stages IIIA, IIIB and IV in 3, 14 and 25 cases. The objective responses included a partial response (PR) 8/41 (19.5%), a stable disease 15/41 (36.6%) and a progressive disease 18/41 (43.9%). The median time-to progression (TTP) and survival were 4 months, ranging from 2 to 14 months, and 8 months, ranging from 2 to 17+ months, respectively. Grade 3 neutropenia was seen in 19% of the patient, and there was no grade 4 neutropenia or episodes of febrile neutropenia. No grade 4 thrombocytopenia or other grade 3/4 non-hematological toxicities were observed. CONCLUSION: The combination of gemcitabine/vinorelbine is active and well tolerated in patients with advanced NSCLC having failed prior taxane/platinum therapy.

The Effect of ZD 1839 (Iressa(R)) in the Treatment of Refractory Non Small Cell Lung Cancer.

PURPOSE: The aim of this study was to evaluate the efficacy and the safety of ZD 1839 (Iressa(R)) as a 3rd or 4th line chemotherapy regimen in NSCLC patients who are refractory to a previous chemotherapy regimen. MATERIALS AND METHODS: Twenty-five patients who were refractory to previous chemotherapy were selected for this study. The eligible patients had an ECOG performance status of 0 to 2, and an appropriate end organ function. ZD 1839 (Iressa(R))250 mg/d was orally administered until the patients experienced disease progression or unacceptable toxicity. RESULTS: Twenty-five patients were analyzed. The median age of the patients was 57 years. The response rate was 12.0% with partial responses in 3 patients. Fourteen patients (56%) remained in the stable disease state and 8 patients progressed. The median overall survival was 9.0 months (95% CI 6.7~11.2). The median progression free survival was 3 months (95% CI 2.2~3.8). Hematological toxicities of grade 3 or 4 neutropenia, anemia and thrombocytopenia were absent. Non-hematological toxicities were grade 2 or 3 skin rashes in 10 (40.0%) patients and 1 (4.0%) patient and grade 3 nausea in 3 (12.0%) patients. No patient failed to continue chemotherapy due to any drug-related adverse events. CONCLUSION: The results suggest that ZD 1839 (Iressa(R)) monotherapy is effective and tolerable as a 3rd or 4th line salvage treatment for NSCLC patients refractory to previous chemotherapy regimens.