Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations

Purpose. Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. Methods/patients. We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. Results. Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39–75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9 %, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2 %, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. Conclusions. Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS (AU)

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Efficacy of platinum combination chemotherapy after first-line gefitinib treatment in non-small cell lung cancer patients harboring sensitive EGFR mutations.

PURPOSE: Gefitinib is an effective first-line chemotherapy for advanced non-small cell lung cancer (NSCLC) patients harboring sensitive EGFR mutations. However, whether second-line platinum combination chemotherapy after first-line gefitinib treatment shows similar effects to first-line platinum combination chemotherapy in these patients remains unclear. Therefore, we here aimed to investigate the efficacy of platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations. METHODS/PATIENTS: We retrospectively evaluated the clinical effects of second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations (exon 19 deletion or exon 21 L858R mutation) at five institutions. All patients were initially treated with gefitinib (250 mg/day) followed by platinum combination chemotherapy as second-line chemotherapy. RESULTS: Between January 2006 and December 2012, 42 patients [8 men, 34 women; median age, 63 years (range 39-75 years)] were enrolled. The overall response rate, disease control rate, and median progression-free survival (PFS) were 26.2, 61.9%, and 5.1 months, respectively, after the second-line treatment. The corresponding values for first-line gefitinib treatment were 69.0, 95.2%, and 11.1 months, respectively. Moreover, second-line platinum combination chemotherapy with pemetrexed or bevacizumab-containing regimens was independently associated with improved PFS. CONCLUSIONS: Second-line platinum combination chemotherapy after first-line gefitinib treatment in NSCLC patients harboring sensitive EGFR mutations was effective and showed equivalent outcomes to first-line platinum combination chemotherapy. After failure of first-line gefitinib therapy, second-line platinum combination chemotherapy with pemetrexed or bevacizumab might result in improved PFS.

Gastrointestinal symptoms in idiopathic pulmonary fibrosis patients treated with pirfenidone and herbal medicine.

Pirfenidone is an antifibrotic agent for patients with pulmonary fibrosis, but this drug has adverse gastrointestinal (GI) effects. The first aim of this study was to assess GI symptoms due to pirfenidone by using a new questionnaire for reflux symptoms and dismotility symptoms. Whether adding herbal medicine of rikkunshi-to improved GI symptoms due to pirfenidone therapy was also investigated. This was a randomized controlled trial performed on 17 IPF patients. The patients were assigned to two groups, and the study period was 8 weeks. The pirfenidone group received pirfenidone therapy for 8 weeks with add-on rikkunshi-to from 4 weeks, while the control group did not receive either of these agents. To assess the effects of RK, plasma levels of acyl-ghrelin and des-acyl-ghrelin, serum KL-6 and surfactant protein-D, and pulmonary function tests were monitored. GI symptoms were most severe during the initial 2 weeks of pirfenidone therapy at a dose of 600 mg/day. Both reflux symptoms and dismotility symptoms deteriorated. Rikkunshi-to improved GI symptoms to the level prior to pirfenidone therapy. Plasma levels of des-acyl-ghrelin and acyl-/des-acyl-ghrelin ratio changed significantly at 8 weeks compared to 2 weeks. GI adverse events due to PFD were most severe in the first 2 weeks of treatment at a dose of 600 mg/day, and both reflux and dismotility symptoms deteriorated, but the drug was well tolerated at 1200 mg/day. Rikkunshi-to contributed to improvement of GI symptoms, but plasma ghrelin levels did not reflect the improvement of GI symptoms.

Serum glycopeptidolipid core IgA antibody levels in patients with chest computed tomography features of mycobacterium aviumintracellulare complex pulmonary disease.

Measurement of serum glycopeptidolipid core IgA antibody (GPL antibody) was recently reported to show a high sensitivity and specificity for diagnosing Mycobacterium avium-intracellulare complex (MAC) pulmonary disease (MAC-PD), but its clinical value has not been confirmed. This study aims to evaluate the seropositive rate in patients with suspected MAC-PD based on chest computed tomography (CT), and to examine whether GPL antibody reflects the extent of lung involvement on CT or the number of bacteria in sputum, retrospectively. Among 66 patients with suspected MAC-PD on CT, 36 patients were negative for MAC by culture and 30 were positive. Sputum grades of MAC were evaluated by fluorochrome microscopy of sputum smears. The lungs were divided into six regions to assess the extent of disease. Serum levels of GPL antibody were measured with an enzyme immunoassay (cut-off value >0.7 U/ml). The GPL antibody positive rate was 19.4% among patients who were negative for MAC by culture versus 73.3% among culture–positive patients. The serum level of GPL antibody was significantly correlated with the sputum smear grade (r=0.43, p less than 0.05) and was also correlated with the number of lung regions showing MAC-PD features on CT (r=0.43, less than 0.05). Some MAC-PD patients may have CT features of MAC with positive level of GPL antibody, although the diagnosis cannot be confirmed by culture. GPL antibody levels reflect the pulmonary burden of MAC, as assessed from the sputum smear grade and number of involved regions on chest CT.

Tracheobronchial stenosis evaluated by inspiratory and expiratory three-dimensional computed tomography and impulse oscillation with three-dimensional color imaging in a patient with relapsing polychondritis.

Patients with relapsing polychondritis (RP) and airway stenosis have difficulty performing conventional spirometry that requires maximum forced expiration. We report a patient with RP who showed progressive severe bronchial stenosis on three-dimensional computed tomography (3D-CT) and impulse oscillation (IOS) with 3D color imaging using a Mostgraph®. The forced oscillation technique using IOS allows within-breath evaluation without forced expiration. A 68-year-old man who had RP presented with dyspnea due to stenosis of the trachea and left main bronchus (lt. mb). Stenting was performed twice in two years. Chest 3D-CT revealed a marked difference in the extent of bronchial collapse during expiration compared with inspiration. The forced expiratory volume in 1 second (FEV1.0), reactance at 5Hz (X5), resonant frequency (Fres), and integrated low frequency reactance area (ALX) measured by IOS showed temporary improvement after placement of the first stent, but respiratory resistance at 5Hz (R5) and 20Hz (R20) remained poor. 3D color images of respiratory resistance obtained with a Mostgraph® already showed high values at the time of diagnosis, resembling the features of chronic obstructive disease (COPD). 3D color images were helpful for interpreting the changes of IOS parameters during the clinical course. In conclusion, 3D-CT in inspiration/expiration and noninvasive IOS with 3D color imaging are useful for assessing airway stenosis in RP while reducing the burden of repeated spirometry.

A case of primary peritoneal serous papillary carcinoma initially presented by massive bilateral pleural effusions.

Primary peritoneal serous papillary carcinoma (PSPC) is a rare primary peritoneal tumor. Clinically, PSPC usually presents with general abdominal discomfort resulting from variable amounts of ascites. In a state of small amounts of ascites, initial manifestation of massive bilateral pleural effusion is unusual. A 76-year-old female nonsmoker with no asbestos exposure complained of dyspnea during exercise. Chest radiograph showed a massive bilateral pleural effusion. Chest computed tomography (CT) revealed irregular pleural thickening and a small amount of ascites. Abdominopelvic CT revealed nodular thickening of the parietal peritoneum, mesenteric or omental nodules, omental cake, and lymphadenopathy in paraaortic regions. Adenocarcinoma cells were found via cytologic examination in bilateral pleural fluids and ascites. Because the primary site of the adenocarcinoma was not found, a surgical biopsy of the right pleural thickening was performed. The final diagnosis was PSPC. The patient was treated with platinum-based chemotherapy. Physicians should be aware of a possibility of PSPC when the radiographic findings show massive bilateral pleural effusion due to pleural carcinomatosis, with high serum levels of CA125.

A phase II study of combined chemoradiotherapy for limited disease-small-cell lung cancer.

A study to evaluate the efficacy of cisplatin, doxorubicin, and etoposide chemotherapy with combined radiotherapy was undertaken in 26 patients with limited disease-small-cell lung cancer. Patients were treated with cisplatin (80 mg/m2) intravenously (i.v.) on day 1, doxorubicin (30 mg/m2) i.v. on day 1, and etoposide (80 mg/m2) i.v. on days 1, 3, and 5, every 4 weeks for four cycles. Thoracic irradiation of 40 Gy in 20 fractions was delivered during 4 weeks to the primary site starting on day 8 of the second cycle of chemotherapy. The objective response rate was 100%. A complete response was observed in 10 patients (38%). The median survival time was 23 months, and the 3-year survival rate was 42%. Seven patients (27%) continued to survive at least 8 years and remain free from disease. Grade III/IV leukopenia was observed in 25 patients (96%). Grade III/IV thrombocytopenia developed in 19 patients (73%). Grade III/IV esophagitis was not seen. Interstitial pneumonitis occurred in two patients. This regimen is effective and has acceptable toxicity for use in the treatment of limited disease-small-cell lung cancer.

[Synchronous primary triple cancers including the lung, stomach, and thyroid: a case report].

A 62-year-old man with synchronous multiple primary cancers involving the lung, stomach, and thyroid was admitted. Initially the patient's chest X-ray showed an abnormal shadow in the right middle-lobe indicating lung cancer. During preoperative examination, gastric cancer of the antrum and angle were detected. Excisional biopsy of the lymph node in the neck after chest surgery revealed thyroid cancer. A middle lobectomy with mediastinal lymph node dissection was performed for lung cancer and the histological diagnosis was moderately differentiated adenocarcinoma, pT4N2M0, stage IIIB. Gastric cancer was treated by endoscopic mucosal resection. Considering the relatively better prognosis of papillary thyroid cancer, we concluded that no further treatment to the thyroid lesion was necessary. In Japan, according to autopsy reports, triple primary cancers are gradually increasing. During the periods 1994 to 1996, the incidence of triple cancers was 0.81% of all autopsy cases reported.

A phase II study of carboplatin-cisplatin-etoposide combination chemotherapy in advanced non-small-cell lung cancer.

It is reported that the combination of cisplatin (CDDP) and carboplatin (CBDCA) is synergistic in vitro. The objective of this study was to evaluate the therapeutic effect and safety of the two platinum compounds in combination with etoposide in the treatment of non-small-cell lung cancer (NSLC). Forty patients were registered. Based on the results of a phase I study, patients were treated with CDDP (80 mg/m2 i.v. on day 1), CBDCA (280 mg/m2 i.v. on day 1), and etoposide (80 mg/m2 i.v. on days 1-3). Of the 40 patients, 30 were men and 10 women. Histology revealed adenocarcinoma(AC) (n = 20), squamous cell carcinoma(SCC) (n = 18), and large cell carcinoma(LCC) (n = 2). Staging: IIIA (n = 3); IIIB (n = 17); and IV (n = 20). A 32.5% overall response rate [13 of 40; 95% confidence interval (CI) 18-47%] was achieved. The response rates in patients with SCC and AC were 55.6 and 10.0% (p < 0.005), respectively. The median duration of response was 47.1 weeks and the overall median survival time was 57.1 weeks. Leukopenia and thrombocytopenia--World Health Organization (WHO) grade IV--occurred in nine and 11 patients, respectively. Nonhematological toxicities were mainly nausea, vomiting, and alopecia. In conclusion, further investigations of this regimen are warranted in the treatment of NSLC.

CYFRA 21-1: an indicator of survival and therapeutic effect in lung cancer.

CYFRA 21-1 is a new tumor marker using two different monoclonal antibodies which recognize the divergent epitope on the N- or C-terminal region of domain 2 of cytokeratin 19 fragment, respectively. In this study, we investigated the relationship between levels of CYFRA 21-1 and survival duration, as well as the efficacy of chemotherapy associated with changes in CYFRA 21-1. Serum samples were obtained from 87 patients with nonoperable lung cancer (35 cases with squamous-cell carcinoma, 33 with adenocarcinoma, 3 with large-cell carcinoma, and 16 with small-cell carcinoma). The cutoff point was set at 3.5 ng/ml. In a CYFRA 21-1 assay, significantly more patients with squamous-cell carcinoma and adenocarcinoma were positive compared to patients with small-cell and large-cell carcinomas (p = 0.0017). Following chemotherapy, blood levels of CYFRA 21-1 decreased significantly in responders versus nonresponders (p = 0.0246). A significant correlation was noted between survival periods and pretreatment levels of CYFRA 21-1 (p = 0.0036). The present study suggests that CYFRA 21-1 might be useful as a possible indicator of survival and therapeutic effect for lung cancer.

Phase I study of a carboplatin-cisplatin-etoposide combination chemotherapy in advanced non-small-cell lung cancer.

Cisplatin (CDDP)-containing chemotherapy has become the mainstay of clinical trials in unresectable non-small-cell lung cancer (NSCLC), but the role of chemotherapy in the routine management of NSCLC remains controversial. We conducted a phase I study with the combination carboplatin (CBDCA), CDDP, and etoposide (Etop) in unresectable NSCLC. CBDCA, at a starting dose of 80 mg/m2, on day 1, was combined with a fixed dose of CDDP (80 mg/m2, day 1) and Etop (80 mg/m2, days 1-3). Escalation was performed after four patients entered at each dose level. If no World Health Organization (WHO) grade 4 toxicity developed after the first cycle in more than half of the patients or WHO grade 3/4 toxicity in more than two thirds, the dose was escalated. The maximum tolerated dose was established at 300 mg/m2 for CBDCA. Thrombocytopenia and leukopenia were the dose-limiting toxicities. No grade 3/4 nonhematologic toxicities were seen. The recommended dose of CBDCA to be combined with CDDP (80 mg/m2, day 1) and Etop (80 mg/m2, days 1-3) is 280 mg/m2. This trial suggests that our combination chemotherapy may be effective in patients with advanced NSCLC. A multicenter phase II study based on these findings is now under way.

A phase II study of 72-hour continuous infusion consisting of cisplatin and 5-fluorouracil for treatment of non-small cell lung cancer.

A combination chemotherapy consisting of a 72-hour continuous infusion of cisplatin (CDDP; 100 mg/m2/72 h) and 5-fluorouracil (5-FU; 3 g/m2/72 h) was conducted for inoperable non-small cell lung cancer (NSCLC). Sixty patients were accepted for this study between June 1988 and December 1990. Forty-seven patients were male (median age 68). Thirty-four patients had stage III and 26 had stage IV disease. The response rate was 25.0% (95% confidence interval, CI, 14.0-36.0%), median survival was 15.7 months. In squamous cell carcinoma, the response rate was 35.5% (95% CI, 18.7-52.3%) and median survival was 15.1 months. In non-squamous cell carcinoma, the response rate was 13.8% (95% CI, 1.2-26.4%) and median survival was 17.7 months. There was a significant difference in response rate (p < 0.01), but no significant difference in survival (p = 0.36). Grade 3 leukopenia was 11.7%, grade 3 and 4 thrombocytopenia was 13.3%. Grade 3 nausea and vomiting were 8.3%. One patient had grade 4 renal toxicity. However, there was no treatment-related death. This regimen was well tolerated. In multivariate analysis, the significant parameters were CEA, performance status and response. In conclusion, 72-hour continuous infusion of CDDP and 5-FU for treatment of NSCLC provides similar response and toxicity as previously reported regimens using CDDP.

[Clinical study of intrapleural administration of pirarubicin (THP-ADM) in the treatment of malignant pleural effusion secondary to lung cancer].

The efficacy of intrathoracic administration of pirarubicin (THP-ADM), a derivative of adriamycin, was evaluated in 20 patients with malignant effusion due to lung cancer. All 20 patients had no previous intrapleural therapy. According to the criteria of ECOG, eight patients were at performance status 1 (P.S.1), nine were P.S.2, and three were P.S.3. Fourteen patients were clinical stage IIIB, and six stage IV. The effusions were first completely drained by thoracocentesis or tube thoracostomy drainage, and 30 mg/m2 THP-ADM was instilled. Overall response rate was 50.0%. The response rate for treatment with tube thoracostomy drainage was 69.2%, which was significantly higher than that for treatment with thoracocentesis (14.3%). Significant difference in survival was not seen between the tube thoracostomy drainage group and the thoracocentesis group. There were no severe side effects. In conclusion, intrapleural administration of THP-ADM with tube thoracostomy drainage was considered to be useful for the control of malignant pleural effusion due to lung cancer.

[A case of intractable status asthmaticus treated by isoflurane inhalational anesthesia and bronchial lavage].

A case of severe asthmatic attack treated by isoflurane inhalational anesthesia and bronchial lavage is reported. A 24-year-old woman was admitted to our hospital with severe asthmatic attack. Although she was treated by intravenous administration of aminophylline and corticosteroids, pulmonary function and consciousness deteriorated. Therefore, she was intubated nasally and mechanically ventilated by IPPV with administration of aminophylline, corticosteroids and epinephrine. Despite this treatment, she remained in status asthmaticus with high airway pressure and barotrauma causing pneumomediastinum and subcutaneous emphysema. On the 3rd hospital day, a system was arranged so that isoflurane could be given in an air and oxygen mixture, and administration was started with a concentration of isoflurane of 1.5%. In addition, bronchial lavage via bronchoscopy was performed in order to clear any mucous plugs. After 24 hours, there was marked improvement of wheezing, airway pressure and arterial blood gas level. Eventually, she was weaned from the ventilator on the 6th hospital day without significant side effects. The use of halothane inhalational anesthetic treatment for status asthmaticus is widely known, but it has serious side effects such as arrhythmia and liver injury. Isoflurane may be the inhalational anesthetic agent of choice in the treatment of status asthmaticus.

[A case of spindle cell (squamous) carcinoma (WHO) of the lung].

A 76-year-old man with spindle cell (squamous) carcinoma of the lung developed fatal respiratory failure after limited thoracic irradiation at a total dose of 18 Gy. He developed severe pulmonary toxicity, which presented as dry cough, dyspnea, and pulmonary infiltrates extending beyond the radiation field. Microscopically, a transitional form of squamous to spindle-shaped cells was observed in the primary tumor, located at right S8. Immunohistochemical examination showed positive staining of spindle cells for keratin, vimentin, and EMA, but not for desmin. These results indicate that the spindle cells had characteristics of squamous epithelial cells, and differed from carcinosarcoma. Distant metastatic lesions were composed of only the spindle cell component.

Clinical effects of cepharanthin (Ceph.) on leukopenia by chemotherapy in lung cancer patients.

In order to examine the clinical efficacy of cepharanthin (Ceph.) for preventing leukopenia caused by chemotherapy in lung cancer patients, a randomized trial was carried out. Subjects were 45 patients with non-small cell lung cancer (NSCLC) receiving initial treatment with cisplatin (CDDP) +adriamycin (ADM) +mitomycin C (MMC). Ceph. was given at a dose of 1 mg/kg to the administration group (Ceph. group) and changes in the peripheral leukocyte count were examined in both the Ceph. and non-Ceph. groups. The Ceph. group showed a reduction in the number of cases with a count nadir less than 3,000/microliters (p less than 0.05), a shortening of the time that leukocyte counts stayed under 2,000/microliters, corresponding to the time in which granulocyte counts were less than 500/microliters (p less than 0.05), and also a reduction of the time for leukocyte counts to recover from nadir to 2,000 or 3,000/microliters (p less than 0.05) measured from the commencement of chemotherapy. These results suggest that administration of Ceph. has an antileukopenic effect in anticancer treatment, and makes it possible to reduce the period of risk for infection, allowing effective regimens to be administered repeatedly in shorter intervals.

Histopathologic prognostic factors in adenocarcinomas of the peripheral lung less than 2 cm in diameter.

The histologic prognostic factors of pulmonary adenocarcinomas of the lung less than 2 cm in diameter were analyzed in 75 patients who had undergone surgical resection. The pathologic stage, lymph node involvement, and pleural involvement were found to be the major determinants of prognosis (P less than 0.01). In addition, other single factors, such as tumor differentiation (P less than 0.01), vascular invasion (P less than 0.01), the degree of collagenization in the fibrotic focus (P less than 0.01), the standard deviation (SD) of nuclear areas (P less than 0.05), and mitotic index (P less than 0.05) correlated significantly with prognosis by the log-rank test on the Kaplan-Meier survival curves of these factors. Patients with dense infiltration of "T-zone histiocytes" survived significantly longer than those with less infiltration (P less than 0.05). Cox's proportional hazard general linear model analysis showed the importance of factors, such as lymph node or pleural involvement and the SD of nuclear area, when the pathologic stage was excluded, and of the mitotic index when all four factors were excluded to emphasize the cellular characteristics. It is possible to predict the postoperative prognosis of patients with small pulmonary adenocarcinoma more precisely by combination of the above histopathologic factors.

[Combination chemotherapy with cis-platinum, adriamycin and mitomycin C (PAM) in the treatment of non-small cell carcinoma of the lung].

Twenty-three patients with inoperable non-small cell lung cancer were treated with a combination chemotherapy of CDDP 100 mg/m2, ADM 30 mg/m2 and MMC 8 mg/m2 (PAM). Ten cases were adenocarcinoma, 9 cases were squamous cell carcinoma and 4 cases were large cell carcinoma. In 21 evaluable cases, partial response was obtained in 47.6%. (The response rates were 40.0% in patients with adenocarcinoma, 50.0% in those with squamous cell carcinoma and 66.7% in those with large cell carcinoma.) Leukocytopenia of less than 4,000/mm3 occurred in 100% of cases, thrombocytopenia of less than 100,000/mm3 occurred in 81.0%, and anemia(fall in hemoglobin over 2.0 g/dl) occurred in 66.7%. A transient elevation of Cr (over 1.5 mg/dl) and/or BUN (over 30 mg/dl) was observed in 23.8%. Nausea and vomiting occurred in almost all patients. No death occurred due to toxicity of PAM. These results demonstrate that PAM is an effective combination chemotherapy in patients with non-small cell carcinoma of the lung.