Phase I study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer.

PURPOSE: This trial was conducted to determine the maximum tolerated dose (MTD), principal toxicity, and recommended dose for phase II study of the combination of nedaplatin and weekly paclitaxel in patients with advanced non-small cell lung cancer (NSCLC). METHODS: Patients with previously untreated NSCLC, either stage IIIB with pleural effusion or stage IV, were eligible if they had a performance status of 0-2, were 75 years or younger, and had adequate organ function. The respective doses of nedaplatin (day 1) and weekly paclitaxel (days 1, 8, and 15) studied were 80/60, 80/70, 80/80, 80/90, and 100/90 (mg m(-2)), repeated every 4 weeks. RESULTS: From May 2004 through June 2005, 21 patients (18 men and 3 women; median age, 63 years; age range, 53-75 years) were enrolled. The MTD was determined to be 100 mg m(-2) of nedaplatin and 90 mg m(-2) of weekly paclitaxel. Dose-limiting toxicities at the MTD were neutropenic fever and hepatic dysfunction. We recommend doses of 80 mg m(-2) of nedaplatin and 90 mg m(-2) of weekly paclitaxel for phase II study. Grade 3-4 hematologic toxicities included neutropenia in 29% of patients, thrombocytopenia in 0%, and anemia in 5%. Although the most frequent non-hematologic toxicity was hepatic dysfunction, all cases were only mildly to moderately severe. Although two patients had grade 3 or 4 pulmonary toxicity due to Pneumocystis carinii pneumonia, these patients recovered after receiving trimetoprim-sulfamethoxazole, steroid therapy, and supplemental oxygen. There were no treatment-related deaths. The overall response rate was 19.0% (95% confidence interval, 5.4-41.9%), and all responses were in patients receiving the recommended doses. The median dose-intensities for nedaplatin and paclitaxel were 91.6 and 87.1%, respectively, of the planned doses. CONCLUSION: This combination chemotherapy is active and well tolerated and warrants phase II study.

Mutant epidermal growth factor receptor undergoes less protein degradation due to diminished binding to c-Cbl.

Gefitinib (Iressa) sensitivity in non-small cell lung cancer (NSCLC) is associated with activating mutations in epidermal growth factor receptor (EGFR). It was reported that autophosphorylation of the mutant EGFR is prolonged compared with wild-type EGFR. To explore the mechanism of sustained autophosphorylation, the mutant and wild-type EGFR degradation activities were examined in NSCLC cell lines. EGFR degradation activity was measured by 125I-EGF. The degradation rate of EGFR was lower in the PC-9 NSCLC cell line, which expressed 15-bp deletion mutant EGFR, compared with that in the PC-14 NSCLC (wild-type EGFR). To clarify the mechanism, the stable transfected cell lines, 293_pEGFR and 293_pdelta15, expressing wild-type and mutant EGFR, respectively, were used. In 293_pdelta15, EGFR degradation and binding of c-Cbl ubiquitin ligase to this receptor were reduced compared with 293_pEGFR. Based on these results, we conclude that the mutant EGFR underwent less protein degradation due to diminished binding to c-Cbl.

[Two cases of successfully treated invasive pulmonary aspergillosis following influenza virus infection].

While invasive pulmonary aspergillosis usually occurs in immunocompromised hosts, it has been described after influenza virus infection in healthy individuals. The first case was a 76-year-old previously healthy woman admitted because of chest pain, cough, sputum, fever, and a chest radiograph abnormality. A transbronchial biopsy specimen showed fungal hyphae. Amphotericin B (AMPH) and Itraconazole (ITCZ) were given, and she improved gradually. A viral test showed a titre of 1/128 to influenza A. Case 2 was a 72-year-old previously healthy man admitted because of cough, fever, chest pain and a consolidation and cavitation on the chest radiograph. Antibiotics were ineffective. Cavitation with a halo sign appeared on the contralateral lung. Because his daughter was infected with Influenza B, we suspected he had been infected with IPA following influenza infection. AMPH and ITCZ and Micafungin sodium were given. His respiratory failure worsened, and on the tenth hospital day he required artificial ventilation; his condition improved gradually, (extubation after 40 days.) A viral test showed a titre of 1/128 to influenza B. IPA must be considered for the differential diagnosis of complications of influenza virus infection.

Phase II study of the combination of gemcitabine and nedaplatin for advanced non-small-cell lung cancer.

We examined the efficacy and safety of the combination of gemcitabine and nedaplatin in patients with untreated advanced non-small-cell lung cancer. Thirty-four patients (24 men and 10 women) with a mean age of 69 years (range, 39-75 years) were treated every 3 weeks with gemcitabine (1,000 mg/m(2) on days 1 and 8) and nedaplatin (100 mg/m(2) on day 1). Four patients had stage IIIB disease and 30 patients had stage IV disease. None of the 33 patients achieved a complete response, but 10 achieved a partial response, for a response rate of 30.3% (95% confidence interval, 15.6-48.7%). One patient could not be evaluated for response because only one course of chemotherapy had been administered due to grade 3 eruption. The median survival time was 9.0 months (range, 1-17 months). Grades 3-4 hematological toxicities included leukopenia in 47% of patients, neutropenia in 62%, thrombocytopenia in 56%, and anemia in 44%. Grades 3-4 nonhematological toxicities included nausea and vomiting in 6% of patients, diarrhea in 3%, and hepatic dysfunction in 9%. There were no treatment-related deaths. The dose intensities were 89.6% and 86.7%, respectively, of the planned doses of gemcitabine and nedaplatin. Our results suggest that the combination of gemcitabine and nedaplatin is an acceptable treatment for patients with previously untreated advanced non-small-cell lung cancer.

The combination of cisplatin and vinorelbine with concurrent thoracic radiation therapy for locally advanced stage IIIA or IIIB non-small-cell lung cancer.

AIMS: The aims of this study were to assess the efficacy and toxicity of concurrent chemoradiotherapy with divided schedule of cisplatin and vinorelbine in patients with locally advanced non-small-cell lung cancer (NSCLC). METHODS: Patients with previously untreated, unresectable, and stage IIIA or IIIB NSCLC were eligible if they had a performance status of 0 or 1, were 75 years or younger, and had adequate organ function. Twenty-six patients (24 men and 2 women; median age, 66 years; age range, 42-75 years) were enrolled. Both cisplatin (40 mg/m(2)) and vinorelbine (20 mg/m(2)) were given on days 1 and 8 every 3 weeks. Beginning on day 2 of chemotherapy, thoracic radiotherapy was given for approximately 6 weeks (2 Gy per fraction; total dose, 60 Gy). RESULTS: Five of the 26 patients achieved a complete response, and 16 achieved a partial response for an overall response rate of 80.8% (95% confidence interval, 60.6-93.4%). The median survival time was 23 months (range, 4-43 months). Overall survival rates at 1 and 2 years were 80 and 56%, respectively. Hematologic toxicities included grade 3-4 neutropenia in 84.6% of patients, grade 3-4 thrombocytopenia in 3.8%, and grade 3-4 anemia in 61.5%. Two patients (7.7%) had grade 3 radiation esophagitis that resolved completely without dilation. Grade 3-4 radiation pneumonitis occurred in two patients (7.7%) and was treated with corticosteroids. Both patients had a good partial resolution of symptoms and radiographic abnormalities. There were no treatment-related deaths. The actual delivered dose intensities for both cisplatin and vinorelbine were 79.5%. Radiotherapy was completed in 96% of patients. CONCLUSION: Concurrent chemoradiotherapy with cisplatin and vinorelbine administered on a divided schedule is effective and well tolerated in patients with locally advanced NSCLC.

Enhancement of sensitivity to tumor necrosis factor alpha in non-small cell lung cancer cells with acquired resistance to gefitinib.

Tumor cells that have acquired resistance to gefitinib through continuous drug administration may complicate future treatment. To investigate the mechanisms of acquired resistance, we established PC-9/ZD2001, a non-small-cell lung cancer cell line resistant to gefitinib, by continuous exposure of the parental cell line PC-9 to gefitinib. After 6 months of culture in gefitinib-free conditions, PC-9/ZD2001 cells reacquired sensitivity to gefitinib and were established as a revertant cell line, PC-9/ZD2001R. PC-9/ZD2001 cells showed collateral sensitivity to several anticancer drugs (vinorelbine, paclitaxel, camptothecin, and 5-fluorouracil) and to tumor necrosis factor alpha (TNF-alpha). Compared with PC-9 cells, PC-9/ZD2001 cells were 67-fold more sensitive to TNF-alpha and PC-9/ZD2001R cells were 1.3-fold more sensitive. Therefore, collateral sensitivity to TNF-alpha was correlated with gefitinib resistance. PC-9/ZD2001 cells expressed a lower level of epidermal growth factor receptor (EGFR) than did PC-9 cells; this down-regulation was partially reversed in PC-9/ZD2001R cells. TNF-alpha-induced autophosphorylation of EGFR (cross-talk signaling) was detected in all three cell lines. However, TNF-alpha-induced Akt phosphorylation and IkappaB degradation were observed much less often in PC-9/ZD2001 cells than in PC-9 cells or PC-9/ZD2001R cells. Expression of the inhibitor of apoptosis proteins c-IAP1 and c-IAP2 was induced by TNF-alpha in PC-9 and PC-9/ZD2001R cells but not in PC-9/ZD2001 cells. This weak effect of EGFR on Akt pathway might contribute to the TNF-alpha sensitivity of PC-9/ZD2001 cells. These results suggest that therapy with TNF-alpha would be effective in some cases of non-small-cell lung cancer that have acquired resistance to gefitinib.

[Infection control in a teaching hospital without a tuberculosis ward].

Approximately 30 cases of tuberculosis are diagnosed in our hospital each year. Because three of our nurses contracted tuberculosis in 1998, we implemented the following control measures for tuberculosis : (1) immediate examination, diagnosis, and treatment in suspected cases; (2) screening of all health-care workers with a two-step tuberculin skin test (TST); (3) examination of all persons exposed to tuberculosis-infected persons; and (4) greater awareness of tuberculosis. We offered prophylactic medications to all exposed persons with a TST reaction greater than 20 mm. These control measures increased the numbers of outpatients who were examined and treated, and decreased the prevalence of tuberculosis among long-term inpatients. High-risk indices also decreased over a 2-year period. Forty-seven staff members showed TST reactions, and 5 of them received prophylactic medication. No cases of tuberculosis developed in staff members exposed to tuberculosis-infected persons. However, tuberculosis developed in one staff member who had a strong TST reaction at the start of employment. In this case, results of TSTs previously administered to all health-care workers was useful for estimating the prevalence of infection. We used a new method for diagnosing tuberculosis in 27 persons believed to be infected. Of these 27 persons, 5 (19%) showed reactions greater than pseudopositive reactions and were given prophylactic medication. Early diagnosis of infected persons, examination of persons exposed to tuberculosis, and greater disease awareness are important measures for monitoring tuberculosis and controlling its spread.

Patients preferences in chemotherapy for advanced non-small-cell lung cancer.

OBJECTIVE: To determine how Japanese patients with lung cancer weigh potential survival, chemotherapy response rate, and symptom relief against the potential toxicity of different treatments in cancer chemotherapy. METHODS AND PATIENTS: We used a questionnaire describing a hypothetical situation about stage IV non-small-cell lung cancer. Seventy-three patients with lung cancer who had received chemotherapy and 120 patients with other respiratory disease as the control group were asked to rate the minimal benefit that would make two hypothetical treatments acceptable. For "chance of cure," "response but not cure," and "symptom relief," the subjects could give answers from 1% to 100% and for prolonging life could give answers from 1 to 60 months. RESULTS: Patients with lung cancer were significantly more likely than were patients with other respiratory diseases to accept either intensive or less-intensive treatments for a potentially small benefit for "chance of cure," "response but not cure," and "symptom relief". The degree of survival advantage that patients require before accepting cancer treatment with its associated toxicity varied widely. If their lives were prolonged 3 months, 19% and 21% of patients with lung cancer would choose to receive intensive and less-intensive treatment, respectively. When the chance of symptom relief was 70%, 73% of patients with lung cancer were willing to choose intensive chemotherapy. Factor associated with patients' choice of chemotherapy in both groups was age. CONCLUSION: Oncologists must consider the substantial range of attitudes to chemotherapy among patients when making treatment decisions and they must give patients the opportunity to be included in this process.

Outcome following surgery for primary lung cancer with interlobar pleural invasion.

PURPOSE: To determine whether interlobar pleural invasion into the adjacent lobe (interlobar P3) should be assessed as T3 according to the tumor-node metastasis classification. METHODS: Surgically treated patients with primary lung cancer (n = 322) were analyzed. RESULTS: Tumors with interlobar P3 had a significantly lower incidence of mass screening detection, a higher occurrence rate of squamous cell carcinoma, and a larger tumor diameter than tumors without interlobar P3. The lymph node metastatic rate did not differ between the patients with and without interlobar P3. The 5-year survival rate of patients with interlobar P3 was 63% and the rates of other patients were 56% with T1 disease, 57% with T2, 31% with T3, and 19% with T4. The survival rate for patients with interlobar P3 was higher than for those with T3 without interlobar P3 (P < 0.05). The 5-year survival rate of the patients with interlobar P3 was lower in adenocarcinoma (39%) than in squamous cell carcinoma (69%, P < 0.01). The results were similar when the analysis was restricted to patients without lymph node metastasis. In adenocarcinoma, the survival rate for interlobar P3 was between the rates for T2 (53%) and T3 (13%) without interlobar P3, whereas in squamous cell carcinoma, the survival rate for interlobar P3 was between the rates for T1 (88%) and T2 (54%) without interlobar P3. CONCLUSION: Tumors with interlobar P3 should be classified as T2 only in squamous cell carcinoma.

[Clinical pathway based on evidence-based medicine (EBM) for chemotherapy for lung cancer].

Recently, combination treatment with cisplatin has been recommended as chemotherapy for lung cancer. However, no clinical pathway for safe and efficient use of anticancer agents has been established. We devised a clinical pathway satisfying evidence-based medicine (EBM) criteria by analyzing case records and the relevant literature. We analyzed 73 case records of hospitalized patients who had undergone chemotherapy for lung cancer on the internal medicine ward of the Showa University Hospital. Grade 3 or higher toxicities of leukopenia, thrombocytopenia, anemia, vomiting, and diarrhea occurred in 30%, 51%, 14%, 5%, 8%, and 1% of patients, respectively. Therefore the checklists for these toxicities were included in the clinical pathway. The National Cancer Institute Common Toxicity Criteria were used for the evaluation of toxicities. According to the guidelines of the American Society of Clinical Oncology and the US Infection Society, the indicated agents and criteria for their use were chosen for supportive cancer treatment. Pharmacists, physicians, and nurses collaborated in making the clinical pathway safe and sufficiently easy for practical use. The final version of the clinical pathway is compatible with EBM and includes items required for safe chemotherapy, which could be helpful in risk management.

Tumor dimension and prognosis in surgically treated lung cancer: for intentional limited resection.

Tumors with a maximum dimension of 3 cm are categorized as T1, whereas those greater than 3 cm are T2 by TNM classification. Some physicians suggest that early-stage peripheral lung cancer should have a maximum tumor diameter of 2 cm and that limited surgery (segmentectomy without lymph node dissection) is acceptable for the patients. In this study, the relationship between the tumor dimension and prognosis was analyzed in 207 patients with surgically treated primary non-small-cell lung cancer (SCLC). The 5-year survival rate of those with tumors 3 cm or less and without lymph node (LN) metastases was 86%, which was significantly higher than that of those with tumors more than 3 cm and without hilar and mediastinal LN metastases (65%) (p < 0.05). However, 33% of the patients with tumors 3 cm or less had LN metastases, and the 5-year survival rate did not differ between those with tumors 3 cm or less (60%) and those with tumors more than 3 cm (54%). Twenty-eight percent of patients with tumors 2 cm or less had LN metastases, and the 5-year survival rate of the patients with tumors 2 cm or less was 62%. The 5-year survival rate of those with tumors 2 cm or less and without LN metastases was 88%. Forty-six patients with tumors 2 cm or less included 5 cases with an intrapulmonary metastasis in the same lobe (11%). In conclusion, a size of 3 cm is an appropriate boundary as the T factor. Because those with tumors 2 cm or less have a relatively high percentage of LN metastases, intraoperative frozen sections of LN should be considered for those undergoing limited surgery for primary non-SCLCs 2 cm or less. Intrapulmonary metastases also should be considered for those undergoing limited surgery even if the maximum dimension of the primary tumor is less than 2 cm.

Phase II study of irinotecan and carboplatin in patients with the refractory or relapsed small cell lung cancer.

We examined the safety and efficacy of the combination of irinotecan plus carboplatin in patients with refractory or relapsed small cell lung cancer (SCLC). Patients with previously treated SCLC were eligible. Patients were treated every 3 weeks with carboplatin (with a target area under the concentration versus time curve of 5 mg min/ml using the Calvert formula on day 1) plus irinotecan (50 mg/m(2) on days 1 and 8). From May 2000 to January 2002, 24 patients were eligible. None of the 22 patients achieved a complete response, but 15 achieved a partial response with an overall response rate of 68.2% (95% confidence interval, 45.1-86.1%). In 13 patients with sensitive disease, the response rate was 92.3% (95% confidence interval, 64.0-99.8%). The median survival time (MST) was 194 days (range 27-605 days). The MST did not differ significantly between patients with sensitive disease (245 days) and those with refractory disease (194 days, P=0.88). One patient died of treatment-related sepsis. Grade 3-4 hematologic toxicities included leukopenia in 58% of patients, neutropenia in 63%, thrombocytopenia in 58%, and anemia in 67%. Grade 3 diarrhea developed in 21% of patients and grade 3-4 infection in 13%. No patients had grade 4 diarrhea or grade 3-4 nausea and vomiting. This regimen is effective and well tolerated in patients with relapsed or refractory SCLC. However, the search for even more active regimens should be continued.

Phase I study of the combination of gemcitabine and nedaplatin for treatment of previously untreated advanced non-small cell lung cancer.

This trial was conducted to determine the maximum-tolerated dose (MTD), principal toxicity, and recommend dose for phase II study of the combination of gemcitabine and nedaplatin in patients with advanced non-small cell lung cancer (NSCLC). Patients with previously untreated NSCLC were eligible if they had a performance status of 0-2, were 75 years or younger, and had adequate organ function. The doses of gemcitabine (days 1, 8) and nedaplatin (day 1) studied were 800/60, 800/70, 800/80, 1000/80, and 1000/100 (mg/m(2)), repeated every 3 weeks. Toxicity could be assessed in all 21 patients enrolled, response could be assessed in 20 patients. The patients were 12 men and 9 women with a mean age of 69 years (range, 47-75 years). Four patients had stage IIIB disease and 17 patients had stage IV disease. The most common histologic type was adenocarcinoma. The MTD was not reached even at the highest doses. The most frequent toxic effects were thrombocytopenia and neutropenia: grade 3 or 4 thrombocytopenia was observed in 19% of patients, and grade 3 or 4 neutropenia in 24% of patients. Nonhematologic toxicities were mild. Grade 3 hepatic dysfunction occurred in 3 patients. Relatively few patients required dose modifications. The median dose-intensities were 91.5 and 93.1%, respectively, of the planned doses of gemcitabine and nedaplatin. The overall response rate was 35% (95% confidence interval, 15.4-59.2%). All responses were seen above level 3. The MTD was not reached even at the highest combination doses. We recommend doses of 1000 mg/m(2) of gemcitabine and 100 mg/m(2) of nedaplatin for phase II study. This combination chemotherapy is active and well tolerated and warrants phase II study.