Gefitinib induction followed by chemoradiotherapy in EGFR-mutant, locally advanced non-small-cell lung cancer: LOGIK0902/OLCSG0905 phase II study.

BACKGROUND: The role of epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor (TKI) induction coupled with standard concurrent chemoradiotherapy (CRT) is unclear in unresectable, stage III, EGFR-mutant non-small-cell lung cancer (NSCLC). Therefore, a phase II trial was conducted to evaluate the efficacy and safety of gefitinib induction followed by CRT in this disease setting. PATIENTS AND METHODS: Patients with unresectable, EGFR-mutant, stage III NSCLC were administered gefitinib monotherapy (250 mg/day) for 8 weeks. Subsequently, patients without disease progression during induction therapy were administered cisplatin and docetaxel (40 mg/m2 each) on days 1, 8, 29, and 36 with concurrent radiotherapy at a total dose of 60 Gy. The primary endpoint was the 2-year overall survival (OS) rate, which was hypothesized to reach 85%, with a threshold of the lower limit of 60%. RESULTS: Twenty patients (median age: 66 years; male/female: 9/11; histology: 20 adenocarcinoma; stage IIIA/IIIB: 9/11; and exon 19/21: 10/10) were enrolled. The 2-year OS rate was 90% (90% confidence interval: 71.4% to 96.8%), indicating that this trial met the primary objective. The overall response rate and 1- and 2-year progression-free survival rates were 85.0%, 58.1%, and 36.9%, respectively. Grade ≥3 adverse events (>10%) included hepatic toxicity during the induction phase and neutropenia and febrile neutropenia in the CRT phase. Radiation pneumonitis grade ≥3 or treatment-related death did not occur. CONCLUSIONS: This is the first prospective study to demonstrate the favorable efficacy and safety of EGFR-TKI induction followed by standard CRT in EGFR-mutant, stage III NSCLC. Further confirmatory studies are needed.

Second primary cancer in survivors following concurrent chemoradiation for locally advanced non-small-cell lung cancer.

Long-term cancer survivors risk development of second primary cancers (SPC). Vigilant follow-up may be required. We report outcomes of 92 patients who underwent chemoradiation for unresectable stage III non-small-cell lung cancer, with a median follow-up of 8.9 years. The incidence of SPC was 2.4 per 100 patient-years (95% confidence interval: 1.0-4.9).

Continued gefitinib treatment after disease stabilisation prolongs survival of Japanese patients with non-small-cell lung cancer: Okayama Lung Cancer Study Group experience.

BACKGROUND: This study aimed to investigate the survival outcome of patients with non-small-cell lung cancer (NSCLC) who had obtained disease stabilisation with gefitinib treatment and to clarify the effect of continued treatment with gefitinib on prognosis. PATIENTS AND METHODS: We reviewed the clinical records of 365 Japanese patients with NSCLC who received gefitinib (250 mg/day). RESULTS: Of 324 (89%) patients assessable for response, 147 (45%) obtained disease stabilisation and 71 (22%) patients achieved an objective response. Overall survival in patients obtaining disease stabilisation was significantly longer than in patients with progressive disease (median survival time 12.1 versus 4.4 months; P <0.0001). In patients obtaining disease stabilisation, those who continued gefitinib treatment until disease progression tended to have longer overall and progression-free survival compared with those discontinuing gefitinib treatment (1-year survival rate 52.1% versus 36.6%, P = 0.08; 1-year progression-free survival rate 31.8% versus 5.2%, P = 0.001). Multivariate analysis showed discontinuing gefitinib was an independent risk factor for progression-free survival (hazard ratio 1.66; 95% confidence interval 1.07-2.56; P = 0.022) but not for overall survival. CONCLUSIONS: Our findings indicate the importance of achieving disease stabilisation with gefitinib treatment and continued gefitinib treatment in Japanese patients with disease stabilisation, although further studies are required to confirm these findings.

Evaluation of various cytological examinations by bronchoscopy in the diagnosis of peripheral lung cancer.

To improve the efficacy of fibreoptic bronchoscopy in the diagnosis of peripheral lung cancer, we evaluated the effectiveness of various techniques for obtaining samples for cytological examination. Between January 1984 and December 2000, flexible fibreoptic bronchoscopy under fluoroscopic guidance was performed in 1372 patients with lung cancer having no visible endoscopic findings. Histological examination of specimens obtained by forceps biopsy and cytological examinations on imprints of biopsy specimens, brushing, selective bronchial lavage, curettage, transbronchial needle aspiration, rinse fluids of the forceps, brush, curette, and aspiration needle, and all fluids aspirated during the bronchoscopic examinations were evaluated for diagnostic power. Using these techniques, the overall diagnostic rate with bronchoscopy was 93.4%. The sensitivity of the histological examination was 76.9%; additional imprint cytology increased the sensitivity to 84.8% (P<0.0001), while additional cytology on the rinse fluid of the forceps increased the sensitivity to 83.7% (P<0.0001). The addition of both imprint cytology and cytology on the rinse fluid of the forceps increased the diagnostic rate to 86.2% (P<0.0001). Our results indicate that cytological examinations of the imprints of biopsy samples and the rinse fluids of the forceps and the brush improve the efficacy of fibreoptic bronchoscopy in the diagnosis of peripheral lung cancer.

A case-control study of lung cancer screening in Okayama Prefecture, Japan.

The effectiveness of lung cancer screening in reducing mortality still remains uncertain. In order to evaluate the efficacy of lung cancer screening, a case-control study was conducted in Okayama Prefecture, Japan. The study area consisted of 34 municipalities where a population-based lung cancer screening had been conducted. Chest X-ray examinations for all participants and sputum cytology for high-risk participants were offered annually. The cases analyzed in this study consisted of 412 individuals aged between 40 and 79 who died of lung cancer. A total of 3490 controls, two to ten for each case matched by gender, year of birth, and living district were randomly collected. Screening histories of cases were compared with those of and matched controls for the identical calendar period prio to diagnosis of the case. Smoking adjusted odds ratio (OR) of death from lung cancer for screened individuals versus unscreened, within 12 months before diagnosis, was calculated as 0.59 (95% confidence interval: 0.46-0.74; P=0.0001). The OR for women (0.39, 95% confidence interval: 0.24-0.64) was lower than that for men (0.67, 95% confidence interval: 0.51-0.87), although both were statistically significant. These results suggest that lung cancer screening contributes to reducing lung cancer mortality by 41%.

Immunohistochemical detection of mutant p53 protein in small-cell lung cancer: relationship to treatment outcome.

We investigated the expression of mutant p53 proteins in small-cell lung cancer (SCLC) immunohistochemically, by identification of stabilized mutant p53 proteins with a much longer half-life than the wild-type protein. Of 103 tumor specimens obtained by transbronchial tumor biopsy for histologic diagnosis, 52 (50%) showed positive staining for p53 protein with a p53 monoclonal antibody, DO-1. Positive staining for p53 protein was not correlated with age, sex, performance status, lifetime cigarette consumption, serum concentration of neuron-specific enolase and extent of disease. Complete response rates in patients with a mutant p53 protein-positive tumor were significantly lower than those in p53-negative patients (25% versus 59%; P=0.0005, by chi-square test). Similarly, survival periods in patients with a mutant p53 protein-positive tumor were significantly shorter than those in mutant p53-protein-negative patients (10.8 months versus 20.6 months; P=0.0001, by generalized Wilcoxon test). Multivariate analysis using Cox's proportional hazards model revealed that the presence of mutant p53 protein is an independent factor associated with differences in overall survival (hazards ratio=2.72; 95% confidence interval, 1.71-4.34; P=0.0001). These observations suggest that the expression of mutant p53 proteins in SCLC may be an important factor predicting poor prognosis.

Prognostic factors in advanced non-small cell lung cancer: elevated serum levels of neuron specific enolase indicate poor prognosis.

BACKGROUND: Non-small cell lung cancer (NSCLC) is resistant to chemotherapy and prognosis of advanced NSCLC patients is considered to be dependent on various prognostic factors. METHODS: We analyzed prognostic factors in patients with advanced NSCLC who had been enrolled in clinical trials conducted by the Okayama Lung Cancer Study Group between 1978 and 1992 using two kinds of multivariate analysis, Cox's multivariate analysis and recursive partitioning and amalgamation (RPA) analysis. RESULTS: The first analysis was performed on 261 patients using 28 variables. Performance status (PS), clinical stage, liver metastasis or serum albumin level was an independent prognostic factor by Cox's analysis. In the second analysis performed on 128 patients having data on neuron specific enolase (NSE), NSE was the most important prognostic factor. Using the RPA method, three subgroups with significantly different survival potentials were defined. Among them, patients with normal serum NSE levels and good PS were found to obtain a markedly favorable prognosis [median survival time (MST) 22.1 months, 3-year survival rate 42.9%], whereas the survival of patients with elevated serum NSE levels and bone metastasis was extremely short (MST 4.7 months, 3-year survival rate 0%). CONCLUSIONS: These results indicate that analysis of prognostic factors including serum levels of NSE is useful for predicting the survival of patients with advanced NSCLC.

[A case of pulmonary plasma cell granuloma with a cavity].

Plasma cell granuloma of the lung is an uncommon and non-malignant neoplasm that may present difficulties in both diagnosis and management. We report a 52-year-old male who was admitted to our hospital due to fever and an abnormal shadow on chest roentgenography. Chest computed tomography revealed a tumor shadow with a cavity in the left upper lobe. However, neither bronchofiberscopy nor serum examinations suggested a diagnosis. Video-assisted thoracoscopic surgery (VATS) was performed and postoperative pathological examination of the resected specimen showed plasma cell granuloma. The postoperative course was uneventful. No recurrence was observed 10 months after the operation. As plasma cell granuloma of the lung is histologically benign, surgery should be performed to preserve the maximal residual lung with no lesion. VATS is the method of choice for treatment of pulmonary plasma cell granuloma.

Fractionated administration of irinotecan and cisplatin for treatment of lung cancer: a phase I study.

A combination chemotherapy of irinotecan (CPT-11) and cisplatin (CDDP) has been reported to be active for lung cancer. In the previous trial, however, diarrhoea and leucopenia became the major obstacle for sufficient dose escalation of CPT-11 to improve the treatment outcome. We conducted a phase I study to investigate whether the fractionated administration of CDDP and CPT-11 at escalated dose was feasible and could improve the treatment outcome. Twenty-four previously untreated patients with unresectable non-small-cell lung cancer (NSCLC) or extensive disease of small-cell lung cancer (SCLC) were eligible. Both CDDP and CPT-11 were given on days 1 and 8, and repeated every 4 weeks. The dose of CDDP was fixed at 60 mg m(-2) and given by 1-h infusion before CPT-11 administration. The starting dose of CPT-11 was 40 mg m(-2), and the dose was escalated by an increase of 10 mg m(-2). The maximally tolerated dose of CPT-11 was determined as 60 mg m(-2) because grade 4 haematological or grade 3 or 4 non-haematological toxicities developed in six patients out of 11 patients evaluated. Diarrhoea became a dose-limiting toxicity. The objective response rates were 76% for NSCLC and 100% for SCLC. The recommended dose of CPT-11 and CDDP in a phase II study will be 50 mg m(-2) and 60 mg m(-2) respectively.

An alteration of ganglioside composition in cisplatin-resistant lung cancer cell line.

Previously we established cell lines resistant to Adriamycin and cisplatin to elucidate the mechanisms involved in acquired drug-resistance. In this study, we investigated ganglioside composition in drug-resistant cell lines. The Adriamycin-resistant cell line, SBC-3/ADM100, exhibited a ganglioside composition ratio similar to that of the parent SBC-3 cells. Densitometric analysis by resorcinol showed a 1.61-fold increase of ganglioside GM2 in SBC-3/ADM100 cells, when compared to the parent SBC-3 cells. The cisplatin-resistant cell line, SBC-3/CDDP, showed a simplified ganglioside pattern, expressing only gangliosides GM3 and GM2. SBC-3/CDDP cells showed a marked increase in ganglioside GM3. These findings suggest that the alteration of ganglioside composition may be actively involved in the acquisition of drug-resistance.

A randomized trial of hybrid administration of cyclophosphamide, doxorubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) versus sequential administration of CAV-PVP for the treatment of patients with small cell lung carcinoma: results of long term follow-up.

BACKGROUND: In an attempt to determine the efficacy of cyclophosphamide, doxorubicin, and vincristine (CAV)/cisplatin and etoposide (PVP) hybrid chemotherapy (HYB), a rapidly alternating chemotherapy, in patients with small cell lung carcinoma (SCLC), the authors conducted a randomized study to compare HYB with CAV-PVP sequential chemotherapy (SEQ). METHODS: Patients in the HYB group received the 3-drug CAV combination on Day 1 and the 2-drug PVP combination on Day 8, repeated every 4 weeks for up to 6 cycles. Patients in the SEQ group received 3 cycles each of CAV and PVP sequentially every 4 weeks, delivered on Days 1 and 8. All responding patients with limited disease (LD) received thoracic irradiation (50 gray) after chemotherapy. RESULTS: Between April 1988 and October 1992, 129 patients were evaluated fully. There were no significant differences in the treatment outcome between patients in the HYB and SEQ groups in terms of the complete response rate (59% for LD patients and 21% for extensive disease [ED] patients in the HYB group vs. 45% for LD patients and 16% for ED patients in the SEQ group), or median survival time (17.9 months for LD patients and 9.7 months for ED patients in the HYB group vs. 20.6 months for LD patients and 12.2 months for ED patients in the SEQ group). CONCLUSIONS: Hybrid CAV-PVP therapy is effective for the treatment of SCLC, but appears to be no better than sequential therapy with the same regimen.

Prognostic factors of small-cell lung cancer in Okayama Lung Cancer Study Group Trials.

In order to elucidate factors influencing the prognosis of small-cell lung cancer (SCLC), we reviewed the records of 253 patients with SCLC and evaluated 20 pretreatment prognostic factors by univariate analysis and Cox's multiple regression analysis. Recursive partitioning and amalgamation (RPA) was employed to identify subgroups with similar survival rates. Cox's multiple regression analysis identified five significant factors: extent of disease, number of metastatic sites, serum albumin, serum lactate dehydrogenase, and presence of weight loss. Among these, extent of disease was the most influential factor. RPA analysis revealed three subgroups predicting significantly different prognoses. The median survival time and 3-year survival rate were 18.4 months and 20.6%, respectively for the good-risk group (limited disease without weight loss), 13.5 months and 9.1%, respectively for the intermediate-risk group (limited disease with weight loss or extensive disease with less than two metastatic sites), and 9.2 months and 0%, respectively for the poor-risk group (extensive disease with two or more metastatic sites). These results will be useful for development of new staging system or subsequent stratification for randomized trials.

[Induction chemotherapy followed by adjuvant surgery (IC-AS) in patients with stage I-II small cell lung cancer (SCLC)].

Ten patients with stage I-II SCLC received IC-AS between 1984 and 1993. As induction chemotherapy, COMP-VAN alternating chemotherapy and CAV-PVP hybrid chemotherapy were administered. The former consisted of a 4-drug combination of cyclophosphamide (CPA), vincristine (VCR), methotrexate (MTX) and procarbazine alternated with a 3-drug combination of etoposide (ETP), adriamycin (ADM) and nimustine every 4 weeks. In the latter, a 3-drug combination of CPA, ADM and VCR given on day 1, and a 2-drug combination of ETP and cisplatin on day 8, were repeated every 4 weeks. All the patients had an objective response, including one complete response by induction chemotherapy. Post-operative pathology revealed SCLC in 4 patients, adenocarcinoma in 2 and no tumor (pathological CR) in 4. Four patients relapsed, and a intrathoracic relapse was experienced in only 2 patients. Six patients have died: 3 from relapsing SCLC, 2 from stomach cancer, and 1 from squamous lung cancer, who was salvaged from relapsing SCLC. The median survival time was 27.5 months, and the 3-year survival rate 37.5%. These results indicate that IC-AS is highly effective for stage I-II SCLC and warrant additional studies comparing IC-AS with chemo-radiotherapy.

[Gingival metastasis of large-cell lung cancer that produced G-CSF].

A 68-year-old man was referred to our hospital for further examination of a gingival mass. Chest radiographs and magnetic resonance imaging disclosed a bulky mass originating in the upper portion of the left lung, in contact with a chronic empyema lesion that first occurred after resection for pulmonary tuberculosis. Examination of a specimen obtained by percutaneous needle biopsy of the mass led to the diagnosis of large-cell carcinoma. Laboratory findings on admission showed marked leukocytosis (48,100/microliter) without evidence of severe a bacterial infection. The level of G-CSF in serum was abnormally high (246 pg/ml, normal value: < 30 pg/ml). Chemotherapy with vindesine, ifosfamide, and cisplatin resulted in shrinkage of the gingival mass, and a decrease in the G-CSF level to 66 pg/ml. Immunohistochemical staining with an anti-G-CSF monoclonal antibody to the primary lung tumor and the gingival mass obtained at autopsy was positive for cytoplasmic G-CSF.

[CAV-PVP chemotherapy and sequential thoracic irradiation (TI) for patients with limited (LD) small cell lung cancer (SCLC)].

In order to assess the effectiveness of sequential TI for the treatment of LD SCLC, we analyzed 69 patients who had received CAV-PVP chemotherapy consisting of cyclophosphamide, adriamycin, vincristine, cisplatin and etoposide, plus sequential TI between 1986 and 1992. TI was delivered at a total dose of 50 Gy, 5 fractions/week for 5 weeks, once patients achieved a maximal response to chemotherapy. Responding patients also received PCI at a total dose of 30 Gy, 5 fractions/week for 3 weeks. Thirty patients achieved CR by chemotherapy and an additional 10 achieved CR after TI, resulting in a CR rate of 58.0%. Of 40 patients achieving CR, 24 have relapsed so far; the primary (in 15) and the brain (in 4) were the major sites of relapse despite TI and PCI. The median survival time was 18.4 months, with a 2-year survival rate of 39% and 3-year survival rate of 20%. Almost all the patients encountered grade 3 or grade 4 leukopenia while receiving chemotherapy, but the toxicity of TI was generally mild. This treatment is useful for patients with LD SCLC.

[In vitro comparison of podophyllotoxin analogues; etoposide, teniposide and NK 611 using human lung cancer cell lines].

In an attempt to predict the antitumor activity of a new podophyllotoxin analogue, NK 611, in the treatment of lung cancer, we compared the drug with etoposide and teniposide using four human small cell lung cancer (SCLC) cell lines, SBC-2, -3, -4, -7, and two non-small cell lung cancer cell lines, ABC-1, EBC-1. In terms of the fifty percent tumor growth inhibitory concentration (IC 50) determined by MTT assay, teniposide was most potent among the drugs. The degree of cross-resistance of each drug was investigated using an etoposide-resistant SCLC subline (SBC-3/ETP), an adriamycin-resistant subline (SBC-3/ADM 100), and a cisplatin-resistant subline (SBC-3/CDDP). As for relative resistant (the ratio of IC 50 for resistant subline to that for the parent subline), NK 611 was least cross-resistant to etoposide, adriamycin, and cisplatin among drugs tested. These results indicate that NK 611 may play a role in a salvage chemotherapy for patients with resistant SCLC.