DNA Cell Biol 2006 May; 25(5): 312-22 (Read article online)

Tsai JR, Chong IW, Chen CC, Lin SR, Sheu CC, Hwang JJ

Nictoine is potentially associated with the onset of chronic obstructive pulmonary disease (COPD) and lung cancer. To gain insights into the molecular mechanism underlying such nicotine-induced conditions, microarray- bioinformatics analysis was carried out in the present study to explore the gene expression profiles in human bronchial epithelial cells (HBECs) treated with 5 muM nicotine for 4, 8, and 10 h. Of 1800 assessed genes overall, 260 (14.4%) were upregulated and 17 (0.9%) downregulated significantly. Gene ontology analysis demonstrated that most of the differentially expressed genes belonged to the category of molecular function, especially to the subcategories of enzyme activity. The integration of obtained information with bioinformatics tools in DAVID and KEGG databases indicated that the greatest number of overexpressed genes was involved in mitogen-activated protein kinase (MAPK) pathway. Membrane array analysis subsequently suggested that both extracellular signal-regulated kinase (ERK) 1/2 and c-Jun-NH(2)-terminal kinase (JNK) signalings but not p38 MAPK signaling were activated in response to nicotine. Pretreatment of HBECs with specific inhibitors against ERK 1/2 and JNK but not p38 could significantly inhibit nicotine-induced interleukin- 8 production. These results suggest that MAPK pathway may mediate the effect of nicotine through ERK 1/2 and JNK but not p38 in HBECs treated with nicotine.

Kyobu Geka 2006 May; 59(5): 426-9 (Read article online)

Shiono S, Masaoka T, Sato T, Yanagawa N

A 75-year-old man admitted to our hospital due to an abnormal X-ray shadow detected during an annual health check-up. Chest computed tomography (CT) revealed 3.0 cm solid nodules with chest wall invasion in the left lung. We could not get a definitive diagnosis by transbronchial lung biopsy or CT-guided needle biopsy. Positron emission tomography (PET)-CT revealed positive findings in the tumor, aortopulmonary window lymph node and splenic flexure. Under a diagnosis of suspected lung cancer, thoracotomy was performed. As intraoperative diagnosis revealed a moderately differentiated squamous cell carcinoma, the patient underwent a left upper lobectomy, mediastinal lymph node dissection, and combined chest wall resection. Pathological stage was T3N2M0, stage IIIA. Ten days after surgery, the patient suffered from ileus and emergent surgery was performed. Subsequent pathological examination revealed lung cancer metastasis in the small intestine.

Clin Exp Metastasis 2006 May 20; (Read article online)

Tannehill-Gregg SH, Levine AL, Nadella MV, Iguchi H, Rosol TJ

The pathogenesis of bone metastases may require the activation of osteoclasts by tumor-secreted factors, which promote important interactions with the bone microenvironment. We utilized an intratibial model of bone metastasis with bioluminescent imaging (BLI) to measure the effect of osteoclast inhibition on the interaction of human lung cancer cells with bone, and on tumor growth. Mice were injected with luciferase-transduced tumor cells (HARA, human pulmonary squamous carcinoma) and divided into three groups: (1) untreated, (2) twice weekly treatment with the bisphosphonate zoledronic acid (ZOL), or (3) osteoprotegerin (OPG). Histomorphometry and imaging were used to evaluate tumor burden, and parameters of osteoclast activity. Mice in the treated groups had increased bone density and decreased osteoclast numbers in nontumor-bearing tibiae. There was greater than 60% reduction in mean tumor volume in both treatment groups when evaluated by histomorphometry (P = 0.06 [OPG], P = 0.07 [ZOL]). However, bioluminescent imaging failed to show a reduction in tumor burden due to wide variability in the data. Osteoclast numbers along tumor-associated bone were significantly increased compared to tumor-free bone, and were not reduced by either treatment. Plasma calcium concentration was increased in all groups. Plasma tartrate-resistant acid phosphatase 5b was reduced in both treatment groups. Plasma PTHrP was significantly increased in the untreated tumor-bearing group, but was not significantly different in the two treatment groups compared to normal mice. OPG or ZOL did not change tumor cell proliferation, but ZOL increased HARA cell apoptosis. OPG and ZOL reduced tumor growth in the tibiae of treated mice, however, PTHrP production by HARA cells may have resulted in a high concentration in the bone microenvironment, partially overriding the antiosteoclast effects of both OPG and ZOL.

Radiat Environ Biophys 2006 May 19; (Read article online)

Veiga LH, Amaral EC, Colin D, Koifman S

Recently a high radon concentration was detected in the underground coal mine of Figueira, located in the south of Brazil. This coal mine has been operating since 1942 without taking cognizance of the high radon environment. In order to assess possible radon-related health effects on the workers, a retrospective (1979-2002) mortality study of 2,856 Brazilian coal miners was conducted, with 2,024 underground workers potentially exposed to radon daughters. Standard mortality ratio (SMR) analysis hints at lower mortality from all causes for both underground (SMR = 88, 95% CI = 78-98) and surface workers (SMR = 96, 95% CI = 80-114). A high statistically significant SMR for lung cancer mortality was observed only in the underground miners (SMR = 173, 95% CI = 102-292), with a statistically significant trend reflecting the duration of underground work. High statistically significant SMRs were observed for pneumonia as a cause of death between both surface (SMR = 304, 95% CI = 126-730) and underground miners (SMR = 253, 95% CI = 140-457). Because mortality from smoking-related cancers other than lung cancer was not found elevated in underground workers and because diesel equipments were not used in this mine, it can be concluded that the enhanced lung cancer mortality observed for underground miners is associated with exposure to radon and radon daughters, rather than other confounding risk factors.

Surg Today 2006; 36(6): 491-8 (Read article online)

Sekine Y, Saitoh Y, Chiyo M, Yasufuku K, Iyoda A, Shibuya K, Iizasa T, Fujisawa T

PURPOSE: The characteristics of tumor extension determine whether pneumonectomy or lobectomy with bronchoplasty should be performed for central lung cancer. We investigated how the characteristics of tumor extension determined the operative methods and the surgical outcomes. METHODS: We conducted a retrospective chart review of 151 patients with positive bronchoscopic findings who underwent lung cancer operations between January 1995 and March 2002. Twenty-five patients underwent pneumonectomy, 88 underwent lobectomy/segmentectomy (Lob/Seg), and 38 underwent Lob/Seg with bronchoplasty. RESULTS: Pathologic staging was higher in the pneumonectomy group than in the Lob/Seg groups, with or without bronchoplasty (P = 0.002). Interlobar extension and hilar lymph node involvement were more frequent, and mucosal invasion was less frequent, in the pneumonectomy group than in the Lob/Seg with bronchoplasty group. The frequencies of all specific pulmonary complications and 30-day mortality were similar among the three groups. The 5-year overall survival rates were 23.7%, 51.5%, and 72.8% for the pneumonectomy, Lob/Seg, and Lob/Seg with bronchoplasty groups, respectively (P = 0.0004). There was a significant difference in survival between patients with mucosal and those with submucosal types of lung cancer (P = 0.0114). CONCLUSIONS: Lob/Seg with bronchoplasty was feasible without a higher risk of operative complications or poorer long-term survival. The nature of tumor extension was important in the selection of operative methods and in predicting survival.

Kyobu Geka 2006 May; 59(5): 359-64 (Read article online)

Oura H, Aikawa H, Handa M, Ube K, Takeuchi K, Tomichi N

The patient was a 75-year-old male who consulted the department of respiratory tract internal medicine in our hospital for left chest pain occurring from the beginning of December 2003. Chest X-ray indicated a tumorous shadow in the left lower lung field. A chest CT also revealed an irregularly shaped mass shadow in the left lower lobe. Since bronchoscopy failed to establish a definitive diagnosis, the patient was referred to our department for surgery to undertake thoracotomy. After left pneumonectomy being performed based on a suspicion of lung abscess, pathological examination of specimen from the resected left lung showed sulfur granules which led to the diagnosis of pulmonary actinomycosis. Because of the diffuse phregmone developing around the surgical wound, benzylpenicillin potassium administration was started, and was continued for a further 6 months on an outpatient basis. Pulmonary actinomycosis is a relatively rare chronic pulmonary infection. It is often difficult to distinguish pulmonary actinomycosis from other pulmonary disease such as lung cancer because of the similarity of their appearance on X-ray or CT, and almost all cases of pulmonary actinomycosis are diagnosed by thoracotomy.

Pharm Res 2006 May 25; (Read article online)

Chen D, Song SH, Wientjes MG, Yeh TK, Zhao L, Villalona-Calero M, Otterson GA, Jensen R, Grever M, Murgo AJ, Au JL

PURPOSE: We reported that suramin produced chemosensitization at nontoxic doses. This benefit was lost at the approximately 10-fold higher, maximally tolerated doses (MTD). The aim of the current study was to identify in patients the chemosensitizing suramin dose that delivers 10-50 muM plasma concentrations over 48 h. METHODS: Nonsmall cell lung cancer patients were given suramin, paclitaxel, and carboplatin, every 3 weeks. The starting chemosensitizing suramin dose was estimated based on previous results on MTD suramin in patients, and adjusted by using real-time pharmacokinetic monitoring. A dosing nomogram was developed by using population-based pharmacokinetic analysis of phase I results (15 patients, 85 treatment cycles), and evaluated in phase II patients (19 females, 28 males, 196 treatment cycles). RESULTS: The chemosensitizing suramin dose showed a terminal half-life of 202 h and a total body clearance of 0.029 L h(-1) m(-2) (higher than the 0.013 L h(-1) m(-2) value for MTD of suramin). The dosing nomogram, incorporating body surface area as the major covariate of intersubject variability and the time elapsed since the previous dose (to account for the residual concentrations due to the slow elimination), delivered the target concentrations in >95% of treatments. CONCLUSIONS: The present study identified and validated a dosing nomogram and schedule to deliver low and nontoxic suramin concentrations that produce chemosensitization in preclinical models.

Ann Surg Oncol 2006 May 23; (Read article online)

Mizuguchi S, Inoue K, Iwata T, Nishida T, Izumi N, Tsukioka T, Nishiyama N, Uenishi T, Suehiro S

BACKGROUND: The purpose of this study was to analyze the clinical significance of serum Sialyl Lewis(x) (SLX) concentrations as a predictor of N2 disease in patients with non-small-cell lung cancer. METHODS: The study included 272 patients with non-small-cell lung cancer who underwent pulmonary resection in our institution between January 1998 and December 2003. Of 272 patients, the serum concentrations of SLX were measured by using a commercially available radioimmunoassay kit. RESULTS: The 5-year survival rates of patients with concentrations of SLX > 38 U/mL and those with lower concentrations were 32% and 69%, respectively (P < .0001). The median serum concentration of SLX in patients with multilevel N2 or N3, single-level N2, and N0/1 disease were 44, 30, and 27 U/mL, respectively. The concentrations of serum SLX in patients with multilevel N2 disease were significantly higher than those in patients with single-level N2 or those with N0/1 disease (Mann-Whitney U-test; P < .0001). Although the sensitivity of SLX for identifying patients with non-small-cell lung cancer was only 24% in all patients, the sensitivity of SLX increased as the N-factor increased; the sensitivity of N0/1 disease was 15%, that of single-level N2 disease was 22%, and that of multilevel N2 or N3 disease was 71%. CONCLUSIONS: High serum concentrations of SLX predicted multilevel N2 disease and the associated poor outcome. Although the sensitivity of serum SLX is not acceptable for use as a screening tumor marker, we suggest that the serum concentration of SLX is useful as a staging marker to determine the strategy of treatment.

Kyobu Geka 2006 May; 59(5): 347-52; discussion 352-4 (Read article online)

Kenzaki K, Sakiyama S, Kondo K, Yoshida M, Nagao T, Nakagawa Y, Takizawa H, Miyoshi T, Tangoku A

In our department, there were 313 thoracic surgeries for primary lung cancer from January 1994 to December 2003. We clinically reviewed for the operative and hospital death (n=18, 5.8%). The patients were 16 males and 2 females (70.6 +/- 5.6 years old). The surgical procedures were 4 pneumonectomies, 13 lobectomies (3 bronchoplasties) and 1 partial resection. The mean interval until postoperative death was 122.5 +/- 156.1 days. There were 5 direct operative deaths within 30 days (1.6%). There were 4 cancer deaths, 2 hemoptyses, 2 operative bleeding, 2 thromboses, 2 cerebral hemorrhages, 1 pyothorax, 1 pneumonia, 1 respiratory failure, 1 multiple organ failure after chemotherapy and 2 unexplained deaths. The patients with pneumonectomy or aged significantly had high mortality. For postoperative complications such as hemoptysis or bleeding, perioperative management that takes these issues into consideration is needed. Furthermore, we must carefully review the preoperative evaluation and combined treatment, because there were many cancer deaths among cases showing early recurrence and metastasis.

Kyobu Geka 2006 May; 59(5): 394-8 (Read article online)

Nishida T, Shoji S, Itoh T, Minami K, Akizuki K, Umekawa K, Nishiyama N

A 47-year-old man was admitted to our hospital for treatment of massive hemoptysis. He was intubated and underwent bronchial arterial embolization because of this deteriorating respiratory state and uncontrollable hemoptysis. Computed tomography (CT) of the chest showed a 1-cm nodular shadow in the peripheral apical lobe (S1) of the right lung. He underwent right upper lobectomy for the purpose of preventing re-hemorrhage as well as making the definitive diagnosis of nodular shadow in S1 of the right lung. Intraoperative pathological examination revealed the nodule as adenocarcinoma, and mediastinal lymphadenectomy was added to the right upper lobectomy. The patient recovered uneventfully, and there has been no sign of recurrence for 15 months after the operation.

Carcinogenesis 2006 May 19; (Read article online)

Quievryn G, Messer J, Zhitkovich A

Recent epidemiological and risk assessment studies have found a very high risk of lung cancer among chromium(VI)-exposed workers even at permissible levels of exposure. However, mechanistic views on the key genotoxic role of transient Cr(V) intermediates were more consistent with the threshold or highly non-linear (heavy dose) models of genetic damage by intracellular Cr(VI). In this work, we examined the production of mutagenic DNA lesions during metabolism of Cr(VI) by its dominant reducer ascorbate (vitamin C) under conditions promoting increased yield of transient Cr forms. We found that slow reductive activation of Cr(VI) by limited concentrations of ascorbate resulted in a greater yield of DCFH-oxidizing Cr intermediates but these species were unable to cause DNA strand breaks. Cr(VI)-ascorbate reactions generated a high number of Cr-DNA adducts that were responsible for all mutagenic responses detected in Cr(VI)-treated pSP189 shuttle plasmids following their replication in human cells. Mutagenicity of DNA damage resulting from the reactions with increased stability of Cr intermediates was approximately 4-times lower relative to the conditions lacking detectable Cr(V) formation. Unlike other reactions, slow reduction of Cr(VI) with ascorbate produced Cr-DNA adducts that were more resistant to dissociation by chelators, suggesting multicoordinate binding of Cr(III) to DNA. Overall, our findings do not support the possibility that increased Cr(V) formation at depleted ascorbate levels modeling heavy dose exposures causes higher levels of mutagenic DNA damage.

Radiat Med 2006 Feb; 24(2): 122-7 (Read article online)

Yamada K, Iwai K, Kawamorita R, Okuno Y, Nakajima T

PURPOSE: We investigated the changes in dose distribution of three-dimensional conformal radiotherapy (3D CRT) during lung tumor treatment. MATERIALS AND METHODS: Ten patients with non-small cell lung cancer who had undergone planning for radical radiotherapy were selected for study. Computed tomography (CT) examination was performed at two time intervals during the course of conformal radiotherapy: t0 Gy at the time of planning and t40 Gy at 40 Gy of treatment. We transferred all the planned beam data at t0 Gy to each t40 Gy CT image. The isodose distribution was recalculated at time t40 Gy for the same beam characteristics. Variations in volumes and dose-volume histograms (DVHs) were analyzed and compared for lung, gross target volume (GTV), and planning target volumes (PTV) between t0 Gy and t40 Gy. A paired t-test was performed to compare the DVH between t0 Gy and t40 Gy. RESULTS: The mean minimum doses for t40 y GTV, and PTV were lower than t0 y. However, there was no significant difference between t0 Gy and t40 Gy (p=0.493, 0.378, respectively). There was a patient whose minimum doses of GTV and PTV were decreased and who had notable improvement of lobar atelectasis after 40 Gy of radiotherapy. Comparison of the percent volume of received dose exceeding 20 Gy (V20) and the mean dose for the total lung revealed that t40 Gy was larger than to Gy (p=0.013, 0.012). CONCLUSION: Incorporation of the time factor into 3D treatment planning is mandatory for frequent reiteration of treatment planning during treatment periods. Clearly, more work in this area should be considered.

Clin Nucl Med 2006 Jun; 31(6): 359-360 (Read article online)

Roscoe KJ, Raja S, Tronic B, Dou Y

A 64-year-old woman presented with hoarseness, and her workup revealed an RUL mass. FDG PET revealed a corresponding single hypermetabolic focus in the RUL with additional thyroid-hypermetabolic focus. The RUL mass resection revealed a primary lung, moderately differentiated scarring adenocarcinoma. Contained within the RUL mass were multiple foci of metastatic papillary thyroid carcinoma. Subsequent thyroid resection revealed papillary thyroid carcinoma of identical histology. This is a rare report of a single positive FDG PET focus containing metastatic papillary thyroid within a primary lung cancer. This case highlights the necessity of histologic confirmation of FDG PET-positive lesions in subsequent patient management.

BMC Public Health 2006 May 23; 6(1): 137 (Read article online)

James PD, Manuel DG, Mao Y

ABSTRACT: BACKGROUND: The concept of 'avoidable' mortality (AM) has been proposed as a performance measure of health care systems. In this study we examined mortality in five geographic regions of Canada from 1975 to 1999 for previously defined avoidable disease groups that are amenable to medical care and public health. These trends were compared to mortality from other causes. METHODS: National and regional age-standardized mortality rates for ages less than 65 years were estimated for avoidable and other causes of death for consecutive periods (1975-1979, 1980-1985, 1985-1989, 1990-1994, and 1995-1999). The proportion of all-cause mortality attributable to avoidable causes was also determined. RESULTS: From 1975-1979 to 1995-1999, the AM decrease (46.9%) was more pronounced compared to mortality from other causes (24.9%). There were persistent regional AM differences, with consistently lower AM in Ontario and British Columbia compared to the Atlantic, Quebec, and Prairies regions. This trend was not apparent when mortality from other causes was examined. Injuries, ischaemic heart disease, and lung cancer strongly influenced the overall AM trends. CONCLUSIONS: The regional differences in mortality for ages less than 65 years was attributable to causes of death amenable to medical care and public health, especially from causes responsive to public health.

Carcinogenesis 2006 May 19; (Read article online)

Lee E, Choi MK, Lee YJ, Ku JL, Kim KH, Choi JS, Lim SJ

The production of prostaglandin E2 (PGE2), a key proinflammatory mediator, is regulated by the availability of its substrate, arachidonic acid (AA), and the activity of the enzyme cyclooxygenase (COX). Increased PGE2 production and COX-2 expression have been frequently observed in specimens from lung cancer patients. Agents that decrease PGE2 production may prevent the initiation and progression of lung cancer. We therefore tested the effects of alpha-tocopherol (alphaTOL) analogues on PGE2 production in human lung epithelial cells. Alpha-tocopheryl succinate (alphaTOS), but not alphaTOL or alpha-tocopheryl acetate (alphaTOA), inhibited the phorbol 12-myristate 13-acetate (PMA)-stimulated PGE2 production in three human lung epithelial cell lines (BEAS-2B, H460 and A549 cells). The effect of these compounds on PGE2 production was not correlated with their antioxidant activities, since alphaTOS alone did not inhibit PMA-induced generation of reactive oxygen species. alphaTOS had no effect on PMA-induced AA release or COX-2 expression, although post-incubation with alphaTOS inhibited COX activity and prostaglandin (PGE2 and PGF2alpha) production in PMA-stimulated cells. alphaTOS also blocked the COX activity in A549 cells with endogenous high levels of COX enzymes in the absence of PMA stimulation. In addition, the ability of alphaTOS to inhibit COX was affected by AA concentration, suggesting that alphaTOS may compete with AA for interaction with COX proteins. These results suggest that alphaTOS inhibits COX activity, thereby inhibiting PGE2 production in human lung epithelial cells, despite the lack of antioxidant activity. Administration of alphaTOS may block inflammatory responses mediated by PGE2, thereby inhibiting the initiation and progression of lung cancer.

Lung Cancer 2006 May 20; (Read article online)

Scartozzi M, Franciosi V, Campanini N, Benedetti G, Barbieri F, Rossi G, Berardi R, Camisa R, Silva RR, Santinelli A, Ardizzoni A, Crinò L, Rindi G, Cascinu S

Pre-clinical data suggested a relationship between inactivation of hMLH1 and hMSH2 and resistance to drugs like cisplatin and carboplatin, but not oxaliplatin. We then hypothesised that NSCLC showing loss of expression of the mismatch repair system (MMR), could be refractory to cisplatin-based, but not to oxaliplatin-based chemotherapy. Immunoistochemical expression of hMLH1 and hMSH2 was analysed on tumour samples from 93 advanced NSCLC, receiving chemotherapy with either cisplatin or oxaliplatin in combination with gemcitabine. Patients showing loss of hMLH1 or hMSH2 expression in >/=50% of tumour cells were deemed MMR-negative (Group A), whereas cases with a normal hMLH1 or hMSH2 expression in >50% of the tumour cells were defined MMR-positive (Group B). No differences in the response and progression rate were found in the whole patients population and in the gemcitabine/cisplatin group for both hMLH1 and hMSH2. In the gemcitabine/oxaliplatin group response rate was 38% and 0% (p=0.04) for patients with or without loss of hMSH2 expression. Median survival according to MMR status in Groups A and B, respectively was: 17 months versus 9 months for hMLH1 (p=0.031) and 10 months versus 9 months for hMSH2 (p=0.8330). Both the difference in response rate and in median survival observed according to MMR status seem to confirm what has been suggested by preclinical studies.

Clin Chest Med 2006 Jun; 27(2): 321-34 (Read article online)

Terman DS, Bohach G, Vandenesch F, Etienne J, Lina G, Sahn SA

There has been renewed interest in the superantigens as antitumor agents with the discovery of a group of bacterial superantigens known as the enterotoxin gene cluster (egc staphylococcal enterotoxins [SEs]). This article discusses the mechanisms by which egc SEs induce tumor killing and pleurodesis. The application of SE homolog and nucleic acid compositions as vaccines and for treatment of established tumors is reviewed. Finally, the use of native SEs ex vivo-intratumorally and intravesicularly administered superantigens against established tumors-is described and the interrelation between superantigen therapy and chemoradiotherapy.

Radiat Med 2006 Feb; 24(2): 128-32 (Read article online)

Hayakawa K, Shiozaki T, Yamamoto A, Kubo S, Osako T

OBJECTIVE: A prospective double-blind randomized study was performed to compare the contrast of vascular enhancement using three dosages of iodinated contrast media for a possible metastatic lesion in the brain. MATERIALS AND METHODS: Sixty-six patients with lung cancer received brain computed tomography (CT) with intravenous administration of iodinated contrast medium (CM). The patients were randomly assigned to receive one of the three types of CM: 30 g iodine, 24 g iodine, and 15 g iodine. Three radiologists judged the degree of vascular contrast enhancement and diagnosed the presence of brain metastasis. The CT numbers in major arteries were also measured. RESULTS: The subjective average scores with standard deviation were 2.06+/-0.48, 1.97+/-048, and 1.44+/-0.43, and the measured average CT numbers with standard deviation (SD) were 168.5+/-39.6, 166.1+/-28.6, and 146.1+/-27.0 HU with 30 g, 24 g, and 15 g iodine, respectively. The scores and the CT numbers in 15 g iodine were less than those with 30 g and 24 g iodine. Brain metastasis was detected in one patient each in groups A and C, and one false-positive case was found in group B. CONCLUSION: CT study with a dose of 24 g iodine showed equivalent quality on vascular enhancement in comparison with a 30 g iodine dose.

Lung Cancer 2006 May 20; (Read article online)

Kakolyris S, Agelidou A, Androulakis N, Tsaroucha E, Kouroussis C, Agelidou M, Karvounis N, Veslemes M, Christophylakis C, Argyraki A, Geroyianni A, Georgoulias V

PURPOSE: To evaluate the efficacy and tolerance of a cisplatin plus etoposide regimen followed by thoracic radiotherapy (TRT) and paclitaxel plus cisplatin consolidation chemotherapy in patients with limited stage small cell lung cancer (SCLC). PATIENTS AND METHODS: Thirty-nine patients with limited SCLC were enrolled onto this study. Patients received three courses of cisplatin 75mg/m(2) IV, day 1 and etoposide 100mg/m(2) IV, days 1-3 (EP regimen), followed by TRT (45-56Gy administered in 15 fractions), and three courses of paclitaxel 175mg/m(2) IV, day 1 and cisplatin, as previously, on day 2 (PP regimen); cycles were repeated every 21 days. RESULTS: All patients were evaluable for toxicity and 34 for response. The overall response rate was 67% (CR: 26%; PR: 41%; intention-to-treat analysis) (95% CI: 53.0-84.2%). After a median follow-up period of 15 months, the median survival time was 15 months, the median time to tumor progression 8.3 months and the 1-year survival rate 53.8%. Grade 3/4 neutropenia occurred in 39% and 36% of patients receiving EP and PP regimens, respectively. The incidence of febrile neutropenia was 5% and 3% for EP and PP regimens, respectively. Other hematologic and non-hematologic toxicities were mild, with the exception of esophagitis occuring in 36% of patients during and/or immediately after radiotherapy. CONCLUSION: Consolidation therapy with PP after sequential EP and thoracic radiotherapy is feasible and well-tolerated; however, the efficacy results are comparable with those previously obtained in the same patients' population using a combination of EP and TRT.

Clin Cancer Res 2006 May 15; 12(10): 3078-84 (Read article online)

Dziadziuszko R, Witta SE, Cappuzzo F, Park S, Tanaka K, Danenberg PV, Barón AE, Crino L, Franklin WA, Bunn PA, Varella-Garcia M, Danenberg KD, Hirsch FR

PURPOSE: Epidermal growth factor receptor (EGFR) mRNA expression and EGFR gene dosage by quantitative PCR in tumor samples obtained from patients with gefitinib-treated non-small cell lung cancer were analyzed in order to determine the association with treatment outcome, clinical, and biological features [EGFR copy number by fluorescent in situ hybridization (FISH), EGFR tyrosine kinase mutations, and EGFR protein expression]. EXPERIMENTAL DESIGN: EGFR mRNA expression was measured by real-time quantitative reverse transcription-PCR in 64 patients, and EGFR gene dosage was analyzed by real-time quantitative PCR in 82 patients from paraffin-embedded specimens. RESULTS: EGFR mRNA expression was higher in responders to gefitinib as compared with nonresponders (P = 0.012). Patients with high EGFR mRNA expression (>5.01) had 43% response probability, whereas patients with low EGFR mRNA expression had 8% response probability (P = 0.006). Patients with high EGFR mRNA expression had longer median progression-free (5.3 versus 2.8 months, P = 0.028) but not overall survival (13.8 versus 10.9 months, P = 0.87). EGFR mRNA expression was higher in FISH-positive patients (P = 0.001) and in patients with positive EGFR immunostaining (P < 0.001) but not in patients with EGFR mutations (P = 0.19). EGFR gene dosage did not predict response (P = 0.54), progression-free (P = 0.73), or overall survival (P = 0.89). EGFR gene dosage was not associated with FISH positivity (P = 0.15), relative mRNA expression (P = 0.27), EGFR mutation status (P = 0.39), and EGFR protein expression (P = 0.35). CONCLUSION: EGFR mRNA expression is a predictive biomarker for response to gefitinib and to progression-free survival after gefitinib treatment. EGFR gene dosage is neither predictive for response nor progression-free nor overall survival.