Prolonged survival in patients with resected non-small cell lung cancer and single-level N2 disease

OBJECTIVES: To test the hypothesis that patients with non-small cell lung cancer and single-level N2 metastases constitute a favorable subgroup of patients with mediastinal metastases, we analyzed the results of the Eastern Cooperative Oncology Group 3590 (a randomized prospective trial of adjuvant therapy in patients with resected stages II and IIIa non-small cell lung cancer) by site of primary tumor and pattern of lymph node metastases. METHODS: Accurate staging was ensured by mandating either systematic sampling or complete dissection of the ipsilateral mediastinal lymph nodes. The overall survival of patients with left lung non-small cell lung cancer and metastases in only 1 of lymph node levels 5, 6, or 7 and right lung non-small cell lung cancer with metastases in only 1 of levels 4 or 7 was compared with that of patients with N1 disease originating in the same lobe. RESULTS: The median survival of the 172 patients with single-level N2 disease was 35 months (95% confidence interval: 27-40 months) versus 65 months (95% confidence interval: 45-84 months) for the 150 patients with N1 disease (median follow-up 84 months, P =.01). However, among patients with left upper lobe tumors, survival was not significantly different between patients with N1 disease and patients with single-level N2 disease (49 vs 51 months, P =.63). The median survival of the 71 patients with single-level N2 metastases without concomitant N1 disease (skip metastases) was 59 months (95% confidence interval: 36-107 months) versus 26 months (95% confidence interval: 16-36 months) for the 145 patients with both N1 and N2 metastases (P =.001). CONCLUSIONS: Survival of patients with left upper lobe non-small cell lung cancer and metastases to single-level N2 lymph nodes is not significantly different from that of patients with N1 disease. The presence of isolate N2 skip metastases is associated with improved survival when compared with patients with both N1 and N2 disease. Survival should be reported by the lobe of primary tumor and metastatic pattern to guide future clinical trial development, treatment strategies, and revisions of the TNM staging system.     

Preoperative induction of CPT-11 and cisplatin chemotherapy followed by chemoradiotherapy in patients with locoregional carcinoma of the esophagus or gastroesophageal junction

BACKGROUND: Patients with localized esophageal carcinoma often develop locoregional and distant disease recurrence. The current study investigated the outcome of a new chemotherapy combination as induction therapy before chemoradiotherapy. METHODS: Forty-three patients with resectable carcinoma of the esophagus or gastroesophageal junction were enrolled. Most of the tumors were endoscopic ultrasonography (EUS) (EUS)T3 (84%) and (EUS)N1 (63%). The patients received < or = 2 6-week cycles of CPT-11 and cisplatin followed by chemoradiotherapy (45 grays with 5-fluorouracil and paclitaxel). Five to six weeks after chemoradiotherapy, the patients underwent staging and surgery. The feasibility, curative resection rates, overall and disease-free survival rates, rate of significant pathologic response, and patterns of disease recurrence were assessed. RESULTS: Of the 43 patients, 39 (91%) underwent an R0 resection. Two patients (5%) died after surgery. A pathologic complete response (pathCR) was observed in 11 (28%) of the 39 patients (or 26% of the 43 patients). In addition, 16 patients (41% of 39 patients or 37% of 43 patients) had < 10% viable tumor in the surgical specimen (pathPR). A comparison of endoscopic ultrasonograpy T and N classifications with surgical T and N classifications demonstrated significant down-staging (P < 0.01). The median survival period of all 43 patients was 22.1 months. Patients who had achieved a pathCR or pathPR had a longer median survival (25.6 months) than those who achieved less than a pathPR (18.5 months; P = 0.52). None of the clinical parameters examined were found to correlate with survival or pathologic response. CONCLUSIONS: CPT-11-based induction chemotherapy resulted in substantial pathCR and pathPR rates, both of which lead to a favorable survival outcome. The three-step strategy needs to be developed further, with the investigation of targeted therapies with chemotherapy and radiotherapy.     

Cullin 3 promotes proteasomal degradation of the topoisomerase I-DNA covalent complex

DNA topoisomerase I (TOP1)-DNA covalent complexes are the initial lesions produced by antitumor camptothecins (CPTs). The TOP1-directed drugs stimulate degradation of TOP1 via the ubiquitin-proteasome pathway. We found that proteasome inhibition prevents degradation of DNA-bound TOP1 and sustains high levels of covalent complexes, thus enhancing CPT-induced cell death. Consistent with this, increased degradation of TOP1-DNA covalent complexes was seen in acquired CPT-resistant cells. We found that the resistant cells showed elevated expressions of Cul3, a member of the cullin family of E3 ubiquitin ligases. The reduction in Cul3 expression by small interfering RNA decreased degradation of TOP1-DNA covalent complexes. Conversely, Cul3 overexpression by stable transfection promoted covalent complex degradation and reduced CPT-induced cell death without affecting basal TOP1 expression levels. These results indicate that Cul3, by promoting proteasomal degradation of TOP1-DNA covalent complexes, becomes an important regulator for cellular CPT sensitivity.     

Evaluation of internal lung motion for respiratory-gated radiotherapy using MRI: Part II-margin reduction of internal target volume

PURPOSE: To analyze the relationship between lung motion and skin surface motion during respiration, determine the uncertainties and variability of such a relationship, and assess the potential of reducing internal target margin for gated radiotherapy. METHODS AND MATERIALS: Three healthy volunteers and four lung cancer patients were recruited in a prospective imaging study using MRI to track the internal lung and external skin motion during breathing. The relationship between the lung and skin motion was modeled using linear regression analysis. The slope of the linear fit and its confidence interval were analyzed for different lung locations, skin surface locations, and breathing patterns from separate imaging sessions. The margins of the internal target volume were calculated based on the residual lung motion during gating and its uncertainties from multiple treatment fractions for the gated treatment. RESULTS: The slope and confidence interval of the linear regression from the motion analysis were uniquely defined by the locations of the lung, skin surface, and breathing patterns. Statistically significant differences were observed among individuals and between different times of measurement. The normal free-breathing motion averaged from all volunteer and patient data was 13.4 +/- 7.4 mm along the superior-inferior (SI) direction and 6.9 +/- 2.6 mm along the anterior-posterior (AP) direction. With simulated respiratory gating, the average margin reduction was 5.5 +/- 4.8 mm and 1.6 +/- 1.0 mm, respectively, along the SI and AP directions (or 36% +/- 15% and 25% +/- 14%, respectively, relative to free-breathing motion). CONCLUSION: Because respiratory movement is rather complex, the relationship between the lung and skin surface motion is affected by many anatomic and physiologic factors. The reduction of internal target margin and efficacy of the free-breathing gating technique should be assessed for individual cases.     

Feasibility of sparing lung and other thoracic structures with intensity-modulated radiotherapy for non-small-cell lung cancer

PURPOSE: To investigate the possibility of using intensity-modulated radiotherapy (IMRT) to reduce the irradiated volumes of the normal lung and other critical structures in the treatment of non-small-cell lung cancer (NSCLC) and to investigate the effect of IMRT on the potential of spreading low doses to large volumes of normal tissues in such treatment. METHODS AND MATERIALS: A retrospective treatment planning study was performed to compare IMRT and conventional three-dimensional conformal radiation therapy (3D-CRT) for 10 NSCLC patients (Stage I-IIIB). In the IMRT plans, three to nine coplanar beams were designed to treat 95% of the planning target volume with 63 Gy and to minimize the volumes of the normal lung, esophagus, heart, and spinal cord irradiated above their tolerance doses. The two types of plans were compared with respect to the planning target volume coverage, dose-volume histograms, and other dosimetric indexes of the normal structures. RESULTS: Comparing the nine-beam IMRT plan with the 3D-CRT plan, the percentage of lung volume that received >20 Gy and the mean lung dose were reduced for all cases, with a median reduction of 8% and 2 Gy, respectively. An additional reduction of the >5-Gy volume and >10-Gy volume for the lung and thoracic tissue was more difficult with IMRT, although still possible using fewer beams in IMRT. The integral dose to the entire thorax was equivalent and even reduced for 8 of 10 cases using IMRT. CONCLUSION: It is possible to reduce the volumes of low doses (such as the >10-Gy volume and >20-Gy volume) for thoracic normal tissues using IMRT. The increased integral dose and low-dose volumes can be avoided for IMRT if such concerns are addressed carefully in the inverse planning process and with optimization of the IMRT beam configuration.     

Development of a novel photosensitizer, talaporfin sodium, for the photodynamic therapy (PDT)

Recently, in Japan, a novel photosensitizer, talaporfin sodium was developed for the photodynamic therapies of various diseases including malignant tumors. At the same time, a diode laser device, Panalas 6405, to be used for this therapy was developed. Talaporfin was first extracted and refined from plant chlorophyll and was found that the skin photosensitivity caused by drug disappeared faster than the existing photosensitizer. Clinically, in the patients with early lung cancer, the complete response was obtained in 85.7% of the lesions (36/42 lesions) by the administration of 40 mg/m2 followed by laser irradiation at 100 J/cm2 4-6 hours later. The sensitivity disappeared mostly within 2 weeks.     

Nationwide surveillance of parenteral antibiotics containing meropenem activities against clinically isolated strains in 2002

The antibacterial activity of meropenem (MEPM) and other parenteral antibiotics against clinical isolates of 899 strains of Gram-positive bacteria, 1500 strains of Gram-negative bacteria, and 158 strains of anaerobic bacteria obtained from 28 medical institutions during 2002 was measured. The results were as follows; 1. MEPM was more active than other carbapenem antibiotics against Gram-negative bacteria, especially against enterobacteriaceae and Haemophilus influenzae. MIC90 of MEPM against Pseudomonas aeruginosa was the lowest of the drugs tested. MEPM showed low cross-resistant rate against both imipenem-resistant P. aeruginosa and ciprofloxacin-resistant P. aeruginosa. MEPM was active against most of the species tested in Gram-positive and anaerobic bacteria, except for multi-drug resistant strains including methicillin-resistant Staphylococcus aureus (MRSA), methicillin-resistant Staphylococcus epidermidis (MRSE). 2. The proportion of extended-spectrum beta-lactamase (ESBL) strains was 3.1% (4 strains) in Escherichia coli and 1.9% (2 strains) in Klebsiella pneumoniae. Carbapenems including MEPM were active against these ESBL strains. In conclusion, the results from this surveillance study suggest that MEPM retains its potent and broad antibacterial activity and therefore is a clinically useful carbapenem; at present, 7 years after available for commercial use.     

Epidermal growth factor receptor as a target to improve treatment of lung cancer

Despite considerable efforts to reduce tobacco use, lung cancer remains the most common cancer in both men and women. Recent advances in radiation therapy and chemotherapy for lung cancer have yielded encouraging results, but survival in patients with locally advanced non-small-cell lung cancer (NSCLC) remains poor. As more and more molecular changes and their importance in malignant tissues continue to be characterized, approaches to target those aberrant pathways are being actively explored. The epidermal growth factor receptor (EGFR) is commonly overexpressed in NSCLC, particularly squamous cell carcinoma, and has been implicated in the development and progression of this disease, although a clear correlation with prognosis has not been established. Several different strategies have been developed to target and block the EGFR and its downstream effects, and some of them have been intensively studied in preclinical and clinical studies as a single-agent approach or in combination with radiation therapy or chemotherapy. In this article, we review the role of EGFR in lung cancer, as well as preclinical and clinical data on strategies to interfere with EGFR signaling alone or in combination with chemotherapy, radiation, or both.