KEY QUESTIONS:

• Imaging: Can these small pulmonary lesions be classified with sufficient accuracy (sensitivity and specificity), based purely on imaging and non-biopsy criteria, such that therapeutic decisions can be made and clinical trials designed based on this data alone without the need for invasive interventional procedures? What technologies need to be developed to accomplish this, and how should these techniques be validated?
  
  
• Pathology: How should the precursor lesions be defined and categorized, and how can diagnosis and accurate assessment of small lesions be improved? What studies need to be conducted to better understand the biology and natural history of these lesions?
  
  
• Surgery: With the currently limited amount of information about the natural history of these lesions and the concern that traditional surgical approaches may be excessive, what information is necessary to define the most appropriate surgical therapy for small screening-detected lung cancers, and how can novel surgical techniques (such as thorascopic resection, sentinel node biopsy, etc.) best be characterized and studied?
  
  
• Radiotherapy: What role can primary or adjunctive radiotherapy play in the treatment of small pulmonary lesions? How best should novel radiotherapeutics such as stereotactic radiosurgery, intraoperative brachytherapy, and radiofrequency ablation be studied in patients with early screening-detected lung cancer?
  
  
• Chemotherapy: Can novel molecularly-targeted agents alter the clinical course of patients with early lung cancers, and can these agents impact on the subsequent development of second malignancies?

KEY RECOMMENDATIONS:

The following is a summary of the Key Recommendations from each of the discussion sections. It was a central tenet from the entire group that since much is unknown about this clinical entity, all patients should be considered for, and offered inclusion in, clinical studies so that a better understanding of the biology, natural history, and therapeutic approaches for these small pulmonary lesions can be established.

IMAGING

• To develop radiographic methods to allow improved delineation and prediction of the biologic nature (i.e., malignant vs. benign) of small pulmonary lesions. To accomplish this, enhanced imaging research components should be included in preclinical and clinical trials. This should include both:
  
  • Rodent imaging with serial respiratory gated lung images in living mice.
    
  • Human imaging in the context of phase I-III clinical trials.
    
    
• In terms of CT screening, there is need for standardization of methods, both for acquisition of the imaging data and for measurement of lesion size. There is also a need to develop and validate new low-radiation dose screening methods.
  
  
• Development of a carefully assembled and documented database.
  
  • Must be a continuing effort that evolves as the technology evolves.
    
  • Needs to contain information regarding the location and biopsy pathology of the screened lesions.
    
  • Special attention should be paid to the ground glass opacities (GGO's or non-solid lesions) to determine their natural history and whether these can be utilized as surrogate endpoints in lung cancer prevention trials.
    
    
• Need for algorithm development and validation, both for the machine algorithms that provide measurement and characterization of the lesions as well as care algorithms to develop validated recommendations for patient care based on characteristics of the lesion as well as the patient. This will need to be based on follow-up data from a large number of patients with screened lesions.
  
  
• Need studies to validate the reliability of the radiographic measurement in vitro and in vivo. This validation needs to be performed across machine types and manufacturers as well as across image acquisition methods so that studies can be compared across centers.
  
  
• Older experiments should be restudied with new high-resolution CT techniques. These studies should include investigation of characteristics that may give us additional information about these screened lesions including lung vascularity, lung compliance, ventilation, and structure.
  
  
• In terms of PET/SPECT, need to develop improvements so that small screened lesions can be detected. Also need to study ways to control for movement/respiration. Need work to develop new tracers with greater specificity, in order to label specifically the tumor rather than non-specific glucose metabolism. These would need to be validated in small pulmonary lesions.
  
  
• Improvements in needle design for transthoracic biopsy of small pulmonary lesions. Studies also need to be done to define the potential role(s) of thermal ablation methods for treatment of screened lesions.

PATHOLOGY:

• Diagnostic and Prognostic Assessment:
  
  • Development of standardized approaches to specimen collection and handling so that specimen quality would be uniform.
    
  • Development of standardized diagnostic criteria and definitions for small screened lung lesions, particularly for precursor lesions such as atypical adenomatous hyperplasia.
    
  • Explore and develop molecular markers for small precursor lesions (e.g., FISH, aneuploidy, gene expression etc.).
    
  • Develop and study techniques to molecularly assess resection margins.
    
    
• Multi-institutional Pathology Registry of small screened pulmonary lesions:
  
  • Correlated with clinical history and long-term outcome as well as radiology imaging data.
    
  • Utilize this resource to develop a high-resolution pathology image database.
    
  • Make pathology tissues from this resource available for molecular studies of precursor and malignant lesions, including surrounding normal tissue, primary lesions, and recurrent/metastatic lesions.
    
  • Development of tissue arrays of small pulmonary lesions for evaluation of molecular markers.
    
  • Develop a panel for pathology review of small pulmonary lesions for further development of standardized diagnostic/pathologic criteria.
    
  • Relational database for correlating pathology, radiology, molecular information, and clinical outcomes.

SURGERY

• Because of the lack of information regarding the natural history, pathology, and imaging characteristics of small screening detected pulmonary lesions, large scale surgical trials are not yet ready to be conducted.
  
  
• A multi-institutional registry, similar to that proposed by the pathology group, should be developed that would be linked to a tissue repository accessible to all investigators. This registry should include imaging information, pathologic data, treatment information, and long-term clinical correlation. Development of these databases within this national registry needs to be concerted and standardized
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• The American College of Surgeons Oncology Group could take a leadership role to initiate and lead this effort since many of the tissue collection, pathology, treatment, and follow-up information and issues directly involves thoracic surgeons.

RADIOTHERAPY

• Stereotactic radiosurgery and radiofrequency ablation are potential alternatives to surgery for the treatment of patients with small pulmonary lesions. These modalities should be actively investigated, starting with patients who have poor pulmonary function and/or are otherwise medically ineligible for surgery. Issues that need to be studied in the context of well-designed trials include respiratory and motion correction or gating, radiotherapy field size, maximally deliverable dose, and outcome.
  
  
• The role of radiotherapy as an adjunct to surgical resection should also be further studied in well-designed clinical trials. This includes 3D conformal RT, and intraoperative brachytherapy.
  
  
• Depending on the outcome data from these studies and once these radiotherapy techniques have been further defined and developed, consideration of a randomized trial comparing surgical resection to focused radiotherapy should be entertained.

CHEMOTHERAPY

• Novel clinical trials should be developed to test the impact of molecularly-targeted therapeutics on small screening detected pulmonary lesions, both in terms of primary therapeutic benefit and secondary prevention. Approaches that were discussed as possibilities include a short course or "window" of therapy prior to definitive resection with correlative biologic and clinical outcome studies, as well as studies on indeterminate nodules to examine the impact of therapy on the natural history. It was recognized that this patient population is ideal for novel trials of chemoprevention of second primary aerodigestive malignancies.
  
  
• There was agreement with previous discussion section recommendations that a coordinated national registry would be extremely valuable to further define the natural history of this entity and would facilitate study of the biology, pathology, imaging, and therapeutic aspects of the disease.