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The prognosis of granulocyte colony-stimulating factor( G-CSF) -producing lung cancer is very poor. We present a case of G-CSF-producing locally advanced non-small cell lung cancer successfully treated with chemoradiotherapy. A 65-year-old man presented with a slight fever, general fatigue, and cough. A mass was detected in the right upper lobe of his lung, and it was diagnosed as squamous cell carcinoma by computed tomography (CT) -guided needle biopsy. Laboratory data indicated marked leukocytosis and elevated serum G-CSF levels, and therefore, the tumor was strongly suspected to be G-CSF-producing lung cancer. After systemic evaluation, the patient was treated with concurrent chemoradiotherapy for cT3N2M0, stage IIIA non-small cell lung cancer. Complete response (CR) was achieved, and he remained well with no recurrence of the cancer for over 3 years after treatment. Although immunohistochemical staining results for G- CSF were negative, clinically, the tumor was diagnosed as G-CSF-producing lung cancer.

Non-small cell lung cancer(NSCLC)patients with activating mutations of the epidermal growth factor receptor(EGFR)gene have shown a dramatic response to EGFR tyrosine kinase inhibitors(EGFR-TKI)such as gefitinib and erlotinib. EGFR activating mutations including exon 19 deletion and exon 21 L858R are recognized as markers ofthe sensitivity to EGFR-TKI therapy in NSCLC. However, the emergence of acquired resistance is virtually inevitable, thus limiting improvement in patient outcomes. Several acquired-resistance mechanisms and candidates, including exon 20 T790M secondary mutation, MET amplification, a high-level of HGF expression, PTEN downregulation, FAS-NF-κB pathway activation, epithelial-mesenchymal transition, and conversion to small cell lung cancer, have been identified. Understanding the mechanisms of acquired resistance to EGFR-TKI, followed by the development of molecular targeted drugs that can overcome the resistance, could serve as an important advance for targeting EGFR, which is activated in NSCLC. Further studies should be performed to clarify other mechanisms associated with the acquired resistance to EGFR-TKI. In this review, we summarize recent advances in the therapeutic biomarkers to EGFR-TKI.

In general, chemotherapeutic effects were low for non-small cell lung cancer (NSCLC) in the lung tumor. We examined the accumulation and antitumor effects of hybrid liposomes (HL-23) composed of phospholipid (L-α-dimyristoylphosphatidylcholine: DMPC) and PEG surfactant [polyoxyethylene(23)dodecyl ether: C₁₂(EO)₂₃] on NSCLC cells in vitro. Accumulation of HL-23 including a fluorescence probe [1-Palmitoyl-2-[12(7-nitro-2-1,3-benzoxadiazol-4-yl)amino]dodecanoyl]-sn-Glycero-3-Phosphocholine: NBDPC] was observed for NSCLC cells using a confocal laser microscope, but no accumulation of HL-23 in normal lung cells was observed. Furthermore, inhibitory effects of HL-23 on the growth of NSCLC cells were obtained on the basis of a WST-1 assay. It was also clarified that HL-23 induced apoptosis for NSCLC cells on the basis of Annexin-V binding and TUNEL assay. These results suggest that HL-23 could be applied in effective chemotherapies for NSCLC.

Objective: We evaluated retrospectively single-agent S-1 chemotherapy in non-small cell lung cancer patients in clinical practice., Methods: Sixteen consecutive patients treated with single-agent S-1 for NSCLC between July 2005 and June 2007 at the Department of Thoracic Surgery, Tsuchiura Kyodo General Hospital. The treatment schedule comprised oral administration of S-1 at 80-120 mg/day. One cycle of S-1 consisted of consecutive administration to 14 (10 cases)or 28(6 cases)days followed by a 14-day rest., Results: Patients profiles were: M/F: 11/5, median age 68 years old(range 51-83), PS 0/1/2/3: 2/6/5/3, adeno/squamous/large: 13/2/1, clinical stage 3A/3B/4: 3/4/9, prior chemotherapy regimens 0/1/2/3/4: 2/3/4/5/2, prior surgery/radiation: 12/5 were performed. Median number of delivered cycles was 5 cycles(range 1-13). Grade 3 hematological toxicities were anemia(6%)and thrombocytopenia(6%). Grade 3 non-hematological toxicities were nausea(6%)and vomiting(6%). Response of 13 patients could be evaluated after 2-4 cycles of S-1. Four partial responses were observed, for a response rate of 31%. The survival time was 67-852 days(average 14.0 months), 1-year survival rate was 74.0%, median time to progression was 4.6 m, and 1- year progression free survival was 25.0%., Conclusion: Single-agent S-1 chemotherapy has modest activity and is the one of the important regimens and tolerable for elderly, poor-PS, recurrent patients with NSCLC in clinical practice.

Purpose: A previous large randomized control study(IALT)revealed that cisplatin(CDDP)-based adjuvant chemotherapy was not effective for patients with ERCC1-positive non-small cell lung cancer(NSCLC). We evaluated the chemosensitivity of surgically resected specimens of NSCLC using in vitro chemosensitivity test and searched for promising adjuvant chemotherapy protocols in the ERCC1-positive subgroup of NSCLC., Patients and Methods: Chemosensitivities of 10 anticancer agents including cisplatin were evaluated by histoculture drug response assay(HDRA) using 28 surgically resected NSCLC specimens. ERCC 1 status was evaluated by immunohistochemistry., Results: ERCC1 was positive in 22 and negative in 6 specimens. All ERCC1-negative specimens were sensitive for CDDP in HDRA, and all CDDP-resistant specimens in HDRA showed positive ERCC1 staining. ERCC1 status was significantly correlated with CDDP sensitivity(p=0.01). HDRA showed average 3(0-6)sensitive anticancer agents except for CDDP even in ERCC1-positive specimens., Conclusion: HDRA may provide effective non-platinum adjuvant chemotherapy protocols for patients with ERCC1-positive, i.e. CDDP resistant, NSCLC.

A 78-year-old man had underwent right upper lobectomy for lung adenocarcinoma in July 1998(pT1N0M0, pStage Ia). In January2003, computed tomography showed a tumor in right lower lobe of lung, which grew slowly. He was treated with UFT. In April 2004, computed tomographyshowed multiple nodules in both lung, which was considered of metastasis of lung cancer. The increase of the nodules were observed, and treatment with gefitinib was started. Insertion mutation at EGFR in exon 20 was seen from the primarylung cancer. Since tumor growth occurred despite gefitinib administration, we converted gefitinib into S-1 using 80 mg/day for 28 days, followed by 14 days rest. Chest computed tomographyshowed a partial response. No side effect was observed, and continued internal use of S-1 until January 2007 when it was impossible to continue, and meanwhile, the increase of the tumor was not seen.

Gemcitabine Hydrochloride (hereafter: Gemcitabine) is a new anti-tumor agent being widely used in other countries for treatment of non-small cell lung cancer was recently approved in Japan. The profile of Gemcitabine is considered to be the following 2 points both for non-small cell lung cancer and for pancreatic cancer, of which the study is currently conducted in Japan: high efficacy as foreign data indicate prolongation of survival time and less frequency of serious adverse reactions than other conventional anti-tumor agents. According to the results of Japanese and foreign phase I studies, as clinical pharmacological profile of Gemcitabine, its elimination half-life is rather short such as 20 minutes. Weekly administration by injection over 30 minutes is appropriate since bone marrow suppression and hepatic disorder were frequently observed in case of administration twice a week or injection for more than 60 minutes. Also, population pharmacokinetics results showed a tendency that blood plasma clearance of Gemcitabine was lower in women and aged patients. Dose adjustment depending on gender is not considered to be necessary because the blood plasma clearance amount of Gemcitabine is large enough itself. However, influence caused by aging must be observed continuously in the future. For its profile of mild adverse reactions of Gemcitabine mentioned above, concomitant chemotherapy with other anti-tumor agents is expected be widely conducted in the future, therefore, clinically pharmacological observation of Gemcitabine is important for its appropriate use as well.

A multicenter phase I clinical trial of RP 56976 (docetaxel), a new anticancer drug, was performed with single and repeated doses. Based on the results of phase I clinical trials conducted in the United States and Europe, the starting dose was 10 mg/m2. The dose was subsequently increased to 20, 50, 70 and 90 mg/m2. A dose of 60 mg/m2 was additionally tested. Single administrations of the six dose levels were performed in a total of 27 patients via intravenous drip infusion over one hour. Ten of the patients subsequently received repeated doses at three of the dose levels in the same manner. The dose limiting factor (DLF) of docetaxel is leukopenia (especially, neutropenia). Based on the observation of the DLF, the maximum tolerated dose (MTD) was determined to be 70-90 mg/m2. The white blood cell count reached a nadir about 9.5-19.5 days (median) after administration, and took 7-11 days (median) to recover. Other adverse reactions observed were nausea/vomiting anorexia, alopecia, diarrhea, fatigue and fever, which were all acceptable. The results of this trial suggest that a dosage regimen of 60 mg/m2 at 3- to 4 week intervals is appropriate in an early phase II clinical trial.

A 48-year-old female was admitted complaining of cough and right chest pain. A chest X-ray showed a tumorous mass in the right lower lung field and hilar and mediastinal lymphadenopathy. The patient underwent transbronchial lung biopsy, and was diagnosed as having a malignant tumor. Because a metastatic lesion was detected in the left lung filed, we opted for chemotherapy. The white blood cell count rose to 103,700/mm3 and 190,000/mm3 in the fifth and sixth month after hospitalization, respectively. The serum granulocyte colony-stimulating factor (G-CSF) level by enzyme immunoassay exceeded 1000 pg/ml. The histological diagnosis of large cell carcinoma was made from the specimen obtained by percutaneous needle biopsy of the lung. The carcinoma cells in this specimen, showed positive staining with anti-G-CSF monoclonal antibody.

Eleven inoperable patients with non-small cell lung cancer were treated as a maintenance therapy with oral etoposide 25 mg daily. The toxicity appeared during the chemotherapy were assessed in all cases, but the blood concentration of the drug were measured in 5 cases on the first and the seventh day of treatment. While the peak plasma level (Cmax) was 0.92 +/- 0.43 microgram/ml on the first day and 1.02 +/- 0.30 micrograms/ml on the seventh day of chemotherapy, AUC was 12.3 +/- 5.41 micrograms.hr/ml and 11.9 +/- 4.52 micrograms.hr/ml on the first and the seventh day, respectively. Cumulative effect of the drug did not exist, since in any of these two measurements there was no significant statistical difference between values obtained on the first and on the seventh day. Regarding the toxicity of the drug, bone marrow suppression with abnormal reduction of peripheral white blood cells was observed. Though grade 2 adverse reaction was found in 6 cases, stopping drug administration for 2 weeks, enabled to re-administer the drug. Alopecia and liver or renal injury were not observed, and in spite of the presence of nausea and anorexia in one case, maintenance therapy could continue in all cases. Based on these results we concluded that etoposide can be safely administered as a maintenance therapy on out-patient basis.

A 41-year-old male complaining of fever and left shoulder pain was admitted to our hospital for further examination of an abnormal shadow on chest X-ray film. His laboratory data on admission showed marked leukocytosis and elevation of serum alkaline phosphatase. The diagnosis of large cell carcinoma of the lung was made by percutaneous biopsy and he was staged clinically as T3N0M0. Chemotherapy including CDDP and VDS resulted in resolution of symptoms and normal laboratory data. After three courses of chemotherapy, he underwent left upper lobectomy with chest wall resection. Pathological diagnosis of the resected tumor was large cell carcinoma with giant cells, and he was staged postoperatively as T3N0M0. Since colony stimulating activity was demonstrated in both homogenate of tumor cells and tumor conditioned medium, and preoperative serum granulocyte colony-stimulating factor (G-CSF) was 105 pg/ml, we concluded that leukocytosis in this patient was caused by G-CSF produced by tumor cells. The patient was in good health two years after surgery with no signs of recurrence.

We describe a case of hCG-producing large cell carcinoma of the lung in a 73-year-old man who had gynecomastia associated with high serum concentration of hCG. Serum hCG levels fluctuated in parallel with the response of the cancer to surgery, chemotherapy, and radiotherapy. The patient was admitted to our hospital with a huge mass shadow in the right lung filed on chest X-ray film on July 31, 1989. Physical examination revealed bilateral gynecomastia. Serum hCG and beta-hCG were 1108.0 mIU/ml (Normal less than 2.0) and 31.9 ng/ml (Normal less than 1.0), respectively. Clinical staging was T2N1M0, determined by radioisotope scanning of bone, and CT scans of the chest, brain and upper abdomen. Right upper and middle lobectomy with mediastinal lymph node dissection was performed on August 18, 1989. The tumor, 6 x 6 x 8 cm in size, was located in the middle lobe and was histologically confirmed to be large cell carcinoma of the lung. A few of small nodules found on the surface of the middle lobe at thoracotomy were histologically proved to be pleural dissemination. Metastatic involvement was present in the hilar and mediastinal lymph nodes. The pathological stage was concluded to be T4N2M0. Immunohistochemistry showed positive staining reaction for hCG within some of the tumor cells. Three weeks after the operation, serum hCG had decreased rapidly but did not reach the normal range. Two courses of DDP, VDS, and MMC were given at four week intervals. Following chemotherapy, serum hCG decreased to the normal range. He was discharged from our hospital on November 29, 1989.2+ useful parameter for the evaluation of treatment and the prediction of prognosis.

Cis-Diamminedichloroplatinum (II) (cisplatin) is one of the key drugs in the treatment of solid tumors. Cis-Diammine-1, 1-cyclobutanedicarboxylateplatinum (II) (carboplatin) and cis-diammine (glycolato)-platinum (254-S) are second-generation platinum-coordination complexes developed in recent years not only to reduce nephrotoxicity but also to have antitumor activity equivalent or superior to cisplatin. Comparative pharmacological study among these three compounds was performed. Six different small cell lung cancer (SCLC) and six non-small cell lung cancer (NSCLC) lines were exposed to different concentration of the three platinum compounds, cisplatin, carboplatin and 254-S in colony assay. The IC50 values for cisplatin, carboplatin and 254-wS in SCLC cell lines were significantly lower than those in NSCLC cell lines. In addition, the IC50s for carboplatin were significantly higher than those for cisplatin and 254-S in both SCLC and NSCLC lines. A total of 15 patients entered the pharmacological study. In all, 80 mg/sqm cisplatin, 450 mg/sqm carboplatin, and 100 mg/sqm 254-S were each given to five patients by intravenous drip infusion over 30 min. Ultrafilterable platinum declined biexponentially for carboplatin and 254-S, whereas the free platinum of cisplatin fitted to a monoexponential equation. We reported the equation between nadir platelet count (NPC) and Ccr, by retrospective analysis in 38 "Training Set" patients; [NPC] = 2,783.4 x [Ccr.]- [NPC] = 2,783.4 x [Ccr.]- 64,264.7. To evaluate prospectively the equation in the "Test Set" patient and to refine it. Thirty four patients who entered phase II study of 254-S for NSCLC were prospectively analysed. Significant correlation was observed between observed NPC and predicted NPC which was calculated by the equation (R = 0.51). To refine the equation, all patients in both "Training Set" and "Test Set" were reanalyzed. Simple linear least model is shown as the best fit and refined equation is as follows: [NPC] = 2,201.7 x [Ccr.]-17,695.0. Bioassay was achieved by clonogenic techniques using NCI-H-69 (SCLC cell line) and PC-9 (NSCLC cell line) as target. Biological comparison was performed on the basis of the antitumor activity of patient's plasma using the antitumor index (ATI). The ATIs obtained by bioassay showed better correlation than the AUCs obtained by chemical assay with the clinical response for the three agents against SCLC and NSCLC according to the following equation: [Reported Response(%)] = 11.5668 + 0.0014 x [ATI] (r = 0.97).

We administered vindesine (VDS) as a single agent at a dose of 1.2 mg/m2/day for 5 days by continuous infusion in 6 patients with inoperable non-small cell lung cancer, and studied the pharmacokinetics of VDS. The maximum concentration (Cmax) of VDS was 6.9 ng/ml and the area under the curve (AUC) was 803 ng.hr/ml. The AUC achieved for VDS was 2.5 times higher after continuous infusion than that observed when 3 mg/m2 of VDS was given by bolus iv injection. Among six patients were 2 PR, including one PR achieved using a 5-day continuous infusion of VDS after failure to respond to cisplatin plus VDS (bolus injection). Severe leukopenia was observed, but it was clinically manageable. The AUC exposure of VDS is greater with the longer infusion periods, and this might improve efficacy compared to conventional bolus injection treatments. The need for further studies appears warranted.

We administered cisplatin (CDDP) as a single agent at a dose of 25 mg/m2/day for 5 days by continuous infusion in 15 patients with inoperable non-small cell lung cancer (3 squamous cell carcinoma, 11 adenocarcinoma and 1 large cell carcinoma), and studied the pharmacokinetics of CDDP, the response rate and toxic effects. The maximum concentration (Cmax) of filtrable platinum (Pt) was 0.092 +/- 0.03 microgram/ml and AUC was 9.3 +/- 3.5 micrograms.hr/ml. The response rate was 40% (6/15). Nausea without vomiting was noticed in 53% of patients and vomiting in 27%. Leukopenia (less than 3,000/mm3) was seen in 53%, thrombocytopenia (less than 70,000/mm3) in 27% and anemia (Hb less than 9.5 g/dl) in 67%. Peak serum creatinine greater than 1.5 mg/dl was not observed. The Cmax of the filtrable Pt was low but AUC level was high compared with that in reported data in which CDDP as a single agent was infused at the same dose in short-term infusion. This was presumably associated with the good response rate in this study. The incidence of hematologic toxicity was slightly high, while that of vomiting and nephrotoxicity was rather low. The 5-day continuous infusion appears to be a safe and effective method of CDDP administration for non-small cell lung cancer, and improved therapeutic results may be expected when this is combined with other effective drugs.