T1N0M0 Non-small Cell Lung Cancer Research Articles

Molecular Biologic Staging of Lung Cancer

Clinical and pathologic staging of lung cancer is suboptimal in achieving the goals of assessing prognosis and selecting therapy. Although the technologic developments that allow the generalized use of proteomic and genomic analyses are relatively recent, major progress in understanding the molecular basis of lung cancer has been made. Predicting survival is only the first step in the use of genomics and proteomics. If a reliable gene array or protein profile can be identified that is associated with poor prognosis, these profiles can then be identified and become potential therapeutic targets. It is not difficult to envision the development of a simple serum test that will diagnose a lung cancer perhaps even before it is clinically apparent and at the same time identify the chemotherapeutic agents to which the tumor is sensitive, allowing individually directed treatment. Eventually, a comprehensive staging system should incorporate the prognostic information of biologic variables.

Molecular Biologic Staging and Selection of Therapy for Non-Small Cell Lung Cancer

The optimal staging system achieves accurate assessment of extent of disease, effective prognostic stratification, and selection of appropriate therapy. The staging system for non-small cell lung cancer (NSCLC) provides a framework for the assessment of prognosis and the assignment of therapy for all patients with a new diagnosis of lung cancer, the most common cause of death by malignancy^1. The most recent revision of the lung cancer staging system, which considers the size and location of the primary tumor (T), the involvement of regional lymph nodes (N), and the presence of distant metastases (M), is based on the analysis of a collected database representing all clinical, surgical-pathologic, and follow-up information for 5,319 patients treated for primary lung cancer^2. Similar results have been reported among a population of 6, 670 patients treated in Japan^3. The power of these large databases in predicting prognosis is self-evident. Nevertheless, there is an inherent inaccuracy of this staging process. According to the TNM system, the predicted 5-year survival after complete resection for T1N0M0 NSCLC (stage IA) is only 67%^2. Therefore, 33% of patients with stage IA NSCLC are incorrectly staged at presentation. Even with optimal therapy, these patients will succumb to their disease, predominately from the development of metastatic disease not detected at the time of diagnosis and initial therapy, despite the use of standard staging procedures^4. Similarly, a significant fraction of all patients with Stage Ib or II disease are incorrectly staged, resulting in inaccurate assessment of extent of disease, prognostic stratification, and selection of therapy. Currently, adjuvant chemotherapy has been established as beneficial for selected patients with after complete resection(superscript 5-7); however, the majority of patients will not benefit, from its administration: substantial fractions will die despite chemotherapy or would have survived even without chemotherapy. Molecular biologic staging refers to the assessment tumor markers associated with various oncogenic mechanisms in order to improve the risk stratification provided by conventional TNM staging. Biologic staging may target oncogenes, oncogenic protein products, growth factors, or receptors. The biologic techniques utilized include analysis of DNA, RNA, or protein products. Molecular biologic staging may potentially be applied to the primary tumor, lymph nodes, bone marrow, or serum, in order to establish the diagnosis of malignancy at earlier stage, to assess prognosis, to detect occult metastases, to select therapy, and to predict chemotherapy sensitivity or resistance. The purpose of the assessment of prognostic markers in the primary tumor is to identify patients, or groups of patients, with early stage disease, whose risk of recurrence is sufficiently high enough to justify adjuvant therapy. In addition, the assessment of the primary tumor may also enable more accurate selection of adjuvant therapy, either cytotoxic chemotherapy or targeted therapy. Assessment of lymph nodes may allow identification of micrometastatic disease: occult metastases not identified on routine pathologic examination. Correct assessment of micrometastatic lymph node involvement improves assessment of extent of disease, prognostic stratification, and choice of adjuvant therapy^8. Assessment of bone marrow and serum may identify evidence of occult distant metastatic disease (Stage IV). Identification of these patients would prevent unnecessary surgical resection and allow patients to receive systemic therapy sooner.

Clinically predictive factors of pathologic upstaging in patients with peripherally located clinical stage IA non-small cell lung cancer

Post-surgical pathologic examination often reveals a more advanced state than clinically defined in non-small cell lung cancer (NSCLC), posing the need for careful consideration of a lesser resection. We investigated the predictive factors for the pathologic upstaging in clinical stage IA NSCLC. The clinical features of 253 consecutive patients with peripherally located T1N0M0 NSCLC who underwent complete resection between 1991 and 2004 were investigated in relation to pathologic T- and N-factors. Of the 253 patients, 46 (18.2%) were upstaged after surgery, due to T-factor in 12 patients, N-factor in 32, M-factor in 2 and both T- and N-factors in 1. Among the clinical parameters, a higher level of serum CEA (p=0.0378) and larger tumor size (p=0.0276) were observed in the upstaged patients. Multivariable analysis revealed that tumor size and positive serum CEA were independently associated with pathologic upstaging. When tumor size was greater than 10mm, patients with positive serum CEA (>2.0 ng/ml) showed a significantly higher incidence of pathologic upstaging (29.2%) than the rest (15.5%, p=0.0461). Clinically defined peripheral stage IA NSCLC should be carefully indicated for a lesser resection when positive serum CEA and/or tumors greater than 10mm in size are observed.

High-Dose-Rate Brachytherapy for Small-Sized Peripherally Located Lung Cancer

The demand for minimally invasive therapies is increasing in the treatment of small peripheral non-small cell lung cancer (NSCLC). Twelve patients with T1-2 N0 M0 peripheral NSCLC were treated by high-dose-rate brachytherapy with (192)Ir radioactive source. A (192)Ir source was introduced into the tumors percutaneously in five patients (percutaneous brachytherapy) or transbronchially in seven patients (transbronchial brachytherapy). Whereas irradiation was performed with a single fraction of 20 Gy in percutaneous brachytherapy, it was hypofractionated from 5 x 5 Gy to 2 x 12.5 Gy in transbronchial brachytherapy. Complications were generally mild in all patients, although focal radiation pneumonitis was observed in most patients. Primary recurrence occurred in three patients, including one with a T2 tumor and one treated by brachytherapy as a salvage treatment for recurrence after conformal radiotherapy. When brachytherapy is evaluated as a primary treatment for T1 N0 M0 NSCLC, local control rate is 88.9% and estimated 5-year survival rate is between 60% and 70%. Brachytherapy has a potential to be a method to treat peripheral T1 N0 M0 NSCLC.

Dosimetric verification in participating institutions in a stereotactic body radiotherapy trial for stage I non-small cell lung cancer: Japan clinical oncology group trial (JCOG0403)

A multicentre phase II trial of stereotactic body radiotherapy for T1N0M0 non-small cell lung cancer was initiated in Japan as the Japan Clinical Oncology Group trial (JCOG0403). Before starting the trial, a decision was made to evaluate the treatment machine and treatment planning in participating institutions to minimize the variations of the prescription dose between the institutions. We visited the 16 participating institutions and examined the absolute dose at the centre of a simulated spherical tumour of 3.0 cm diameter in the lung using the radiation treatment planning systems in each institution. A lung phantom for stereotactic body radiotherapy (SBRT) was developed and used for the treatment planning and film dosimetry. In the JCOG radiotherapy study group, the no model-based calculation algorithm or the model-based calculation algorithm with a dose kernel unscaled for heterogeneities were selected for use in the initial SBRT trials started in 2004, and the model-based calculation algorithm with a dose kernel scaled for heterogeneities was selected for the coming trial. The findings of this study suggest that the clinical results of lung SBRT trials should be carefully evaluated in comparison with the actual dose given to patients.

Surgical Results in T2N0M0 Nonsmall Cell Lung Cancer Patients With Large Tumors 5 cm or Greater in Diameter: What Regulates Outcome?

We assessed the surgical results along with the clinical and biological features of nonsmall-cell lung cancer (NSCLC) patients with localized large tumors. The study population consisted of 86 NSCLC patients who underwent complete resection of tumors 5 cm or larger in diameter in stage IB (T2N0M0). We immunohistochemically assessed the expression of angiostatin and endostatin. The median tumor size was 6.0 cm (range, 5 to 14 cm). The operative procedures used were lobectomy in 71 cases, bilobectomy in 8 cases, and pneumonectomy in 11 cases. Fifty patients (58.1%) relapsed during the mean follow-up period of 33.6 +/- 4.5 months. The median disease-free interval was 9 months. Of 44 recurrent patients whose disease-free interval could be identified, 25 patients (56.8%) relapsed within 12 months after the operation. The overall 5- and 10-year survival rates were 42.0% and 24.2%, respectively. Multivariate analysis showed that the degree of pleural involvement and angiostatin expression within the tumor were independent prognostic indicators. The endostatin expression within tumors also had a weaker relationship with outcome. Long-term surgical results were poor and early relapse was common in this cohort. In addition to pleural involvement, the tumor-induced expression of angiostatin and endostatin merit further investigation to gain possible insights into selection of patients who will benefit from surgery as the first line treatment.

Relationship of Tumor Size to Survival in Patients with pT2N0 Lung Cancer

Lung cancer extending beyond 3 cm in diameter without lymph node or distant metastasis is defined as T2. The purpose of this study was to analyze the prognosis based on tumor size for patients with resected T2N0M0 non-small cell lung cancer. The 268 patients who underwent complete resection of a lung tumor > 3 cm in diameter were reviewed retrospectively. They were divided into 3 groups based on tumor size: 3-5 cm, > 5-7 cm, and > 7 cm. There were significant differences in the 5-year survival rates of 61.4%, 47.9%, and 21.9% in each group, respectively. In the two subgroups with tumor sizes 3-4 cm and > 4 cm, the 5-year survival was 63.8% and 48.1%, respectively. Tumors > 4 cm in diameter indicate a poor long-term prognosis.

834 POSTER Planning target volume margins for prostate radiotherapy using daily electronic portal imaging and implanted fiducial markers

To determine the dose to regional nodal stations in patients with T1–3N0M0 non-small cell lung cancer (NSCLC) treated with three-dimensional conformal radiation therapy (3DCRT) without intentional elective nodal irradiation (ENI).Twenty-three patients with medically inoperable T1–3N0M0 NSCLC were treated with 3DCRT without ENI. Hilar and mediastinal nodal regions were contoured on planning CT. The prescription dose was normalized to 70 Gy. Equivalent uniform dose (EUD) and other dosimetric parameters (e.g., V40) were calculated for each nodal station.The median EUD for the whole group ranged from 0.4 to 4.4 Gy for all elective nodal regions. Gross tumor volume (GTV) and the relationship between GTV and hilum were significantly correlated with irradiation dose to ipsilateral hilar nodal regions (P < .05). For patients with GTV ⩾ 30.2 cm3 (diameter ≈ 4 cm) and or having any overlap with hilum, the median EUDs were 9.6, 22.6, and 62.9 Gy for ipsilateral lower paratracheal, subcarinal, and ipsilateral hilar regions, respectively. The corresponding median V40 were 32.5%, 39.3%, and 97.6%, respectively.Although incidental nodal irradiation dose is low in the whole group, the dose to high-risk nodal regions is considerable in patients with T1–3N0 NSCLC when the primary is large and/or centrally located.

Long-term results of high-dose conformal radiotherapy for patients with medically inoperable T1–3N0 non–small-cell lung cancer: Is low incidence of regional failure due to incidental nodal irradiation?

To report the results of high-dose conformal irradiation and examine incidental nodal irradiation and nodal failure in patients with inoperable early-stage non-small-cell lung cancer (NSCLC). This analysis included patients with inoperable CT-staged T1-3N0M0 NSCLC treated on our prospective dose-escalation trial. Patients were treated with radiation alone (total dose, 63-102.9 Gy in 2.1-Gy daily fractions) with a three-dimensional conformal technique without intentional nodal irradiation. Bilateral highest mediastinal and upper/lower paratracheal, prevascular and retrotracheal, sub- and para-aortic, subcarinal, paraesophageal, and ipsilateral hilar regions were delineated individually. Nodal failure and doses of incidental irradiation were studied. The potential median follow-up was 104 months. For patients who completed protocol treatment, median survival was 31 months. The actuarial overall survival rate was 86%, 61%, 43%, and 21% and the cause-specific survival rate was 89%, 70%, 53%, and 35% at 1, 2, 3, and 5 years, respectively. Weight loss (p = 0.008) and radiation dose in Gy (p = 0.013) were significantly associated with overall survival. In only 22% and 13% of patients examined did ipsilateral hilar and paratracheal (and subaortic for left-sided tumor) nodal regions receive a dose of > or = 40 Gy, respectively. Less than 10% of all other nodal regions received a dose of > or = 40 Gy. No patients failed initially at nodal sites. Radiation dose is positively associated with overall survival in patients with medically inoperable T1-3N0 NSCLC, though long-term results remain poor. The nodal failure rate is low and does not seem to be due to high-dose incidental irradiation.

Percutaneous CT-guided 103Pd implantation for the medically inoperable patient with T1N0M0 non-small cell lung cancer: A case report

Three patients with early-stage T1N0M0 non-small cell lung cancer (NSCLC) who had medical contraindications for standard surgical resection were treated with CT-guided percutaneous implantation of 103Pd seeds. The technique was proven safe in this small subset of patients without any complications related to the procedure or during short-term follow-up.

Modified stage I (T1N0M0, T2N0M0), nonsmall cell lung cancer: Treatment results, recurrence patterns, and adjuvant immunotherapy

We analyzed 96 patients who had surgery with T1N0M0 or T2N0M0 nonsmall cell lung cancer (NSCLC) to identify survival rates and recurrence patterns in well-staged patients and to evaluate adjuvant therapy. Preoperative staging included chest x-ray, gallium 67 scanning, and bronchoscopy in all patients. At thoracotomy, multiple mediastinal lymph node sites were routinely sampled. The results included an operative mortality rate of 5.2%, and the actuarial 5-year survival rate of all patients was 70.0%. Survival of T1N0 (n = 44) and T2N0 (n = 47) patients was 72.1% and 68.3%, respectively (p = NS). Survival was not affected by type of surgery, cell type, sex, age, or race. Late death was due to recurrence in 12 patients, a new airway malignancy in three, and a noncancer problem in six. Disease recurred in 15 patients: four (9.1%) T1N0 patients versus 11 (23.4%) T2N0 patients, p less than 0.05. Recurrence was local in four patients and distant in 11. Second lung cancers developed in six patients at a mean interval of 65.7 months after resection. A prospective, randomized trial of systemic immunotherapy with bacillus Calmette-Guerin (BCG) skin scarification was carried out in 29 patients. Survival in those patients receiving BCG was 85.9% compared with 63.9% for control subjects (p = 0.075) and 69.6% for patients not in the study (p = 0.077). The following conclusions can be made: Resection for well-staged, modified stage I NSCLC results in a 5-year survival rate of 70%. Nearly half the deaths are unrelated to recurrence of the original cancer. Recurrences are more frequent in T2N0 patients, but there is no survival difference compared with T1N0 patients. Systemic recurrences are more frequent than local recurrences, and there is an appreciable incidence of second lung cancers. Adjuvant chemotherapy or radiation therapy does not seem justified, but systemic immunotherapy holds sufficient promise to warrant further investigation.