Hypertension and obesity are two disorders that are closely related; each occurs more frequently with the other than in an otherwise normal population. These two disorders, however, exert disparate effects on cardiovascular structure and function. The hallmark of essential hypertension is an increased total peripheral resistance, and hypertensive patients have a contracted intravascular volume and normal cardiac output but an increased left ventricular stroke work due to a high afterload. In contrast, obese patients have an increased intravascular volume, left ventricular filling pressure, cardiac output and a lower total peripheral and renal vascular resistance. Left ventricular adaptation will consist of eccentric hypertrophy in obesity regardless of the level of arterial pressure and concentric hypertrophy in lean hypertensive patients. Although obesity may mitigate the harmful effect of a chronically elevated total peripheral and renal vascular resistance and lessen target organ damage in essential hypertension, the combination of obesity and hypertension presents a double burden to the left ventricle and is associated with systolic and diastolic dysfunction and a propensity for high grade ventricular dysrhythmias. It is not surprising that congestive heart failure and sudden death are common sequelae of obesity hypertension. Weight reduction reduces arterial pressure by decreasing intravascular volume and cardiac output associated with a fall in sympathetic activity and reversal of cardiac hypertrophy. Therefore, weight loss unloads the heart from the two-fold burden caused by obesity and hypertension and should become a major goal in the prevention and treatment of heart disease.

Free radicals (and other toxic metabolites of oxygen) are generated in most cells as a consequence of normal metabolic processes, but cells are protected from injury by antioxidant mechanisms. Several forms of lung injury appear to result from generation of toxic metabolites of oxygen in quantities which exceed the antioxidant capacity of lung cells. Several manipulations which prevent free radical production or accumulation or enhance antioxidant capacity of lung tissue may prove to be useful therapeutically in acute and chronic diseases of the lungs.

Nonsurgical combined approaches of non-small cell lung cancer represent a concept that has only been investigated so far with chemotherapy and radiation therapy. Thoracic irradiation of locoregional disease is associated with a high rate of local control and a 5-10% long-term (5-year) survival; however, distant metastases remain the main cause of failure. This observation suggests that the tumor is often microscopically disseminated at the time of diagnosis. Systemic therapy therefore must be associated to radiation therapy to try to control both the undetectable metastases and the local disease. However, the results reported so far have been disappointing, probably because of the modest activity of the available chemotherapy. Further progress with the combined approach requires new developments in the chemotherapy of non-small cell lung cancer, particularly the introduction of new active drugs.

Computed tomography (CT) is now established as the principal radiographic adjunct to plain film examination in the diagnosis and management of lung cancer. It should be used in the evaluation of every pulmonary nodule to determine whether the nodule is solitary and whether mediastinal metastases are present and to evaluate the mass by assessing its density. In general, nodules with Hounsfield numbers greater than +175 can be presumed to be calcified and, hence, benign. CT is of great value in determining the extent of lung cancer and at present the best imaging modality for evaluating mediastinal lymph nodes. Spread of tumor to mediastinal nodes is evaluated on the basis of node size. Nodes less than 1.0 cm in diameter are considered normal, 1.0-1.5 cm suspicious for tumor, and greater than 1.5 cm have a high probability of being malignant. Node size, however, is dependent on location in the mediastinum and whether infection is present in the lung. Size criteria alone should not be used to deny surgery.

Bronchoscopic phototherapy is available now for 2 distinct categories of tracheobronchial cancer: roentgenographically occult superficial squamous cell carcinoma and advanced malignancy causing significant airway obstruction. Laboratory and clinical experience show that the photodynamic effect of hematoporphyrin derivative phototherapy (HpD-PT) may be useful for treating superficial cancers that penetrate less than 5 mm into bronchial mucosa. The larger, obstructing cancers are better managed by high-power laser sources, such as the YAG laser, which are effective by hyperthermal photocoagulation, thermal necrosis, and tissue vaporization.

On the occasion of this Fourth World Conference on Lung Cancer, I am privileged to present the opening keynote address. This presentation has been sponsored by the Ontario Cancer Treatment and Research Foundation. In 1952, the Foundation established an annual lectureship in memory of one of their prominent physicians. Dr. Gordon Earle Richards was one of Canada's pioneer radiologists and radiotherapists who was appointed Director of the Institute of Radiotherapy at Toronto General Hospital at a time when radium and high-voltage x-rays were just coming into common use for the treatment of malignant disease. He established an international reputation for his contributions to clinical radiotherapy, and was subsequently appointed Professor of Radiology at the University of Toronto. He was Managing Director of the Ontario Cancer Treatment and Research Foundation between 1945 and 1949. I wish to thank the Foundation for the privilege of presenting the 33rd Gordon Richards Memorial Lecture.

The most important role of radiation therapy for carcinoma of the lung is its contribution to cure. Important technical advances in radiation therapy have been made that, along with advances in understanding the natural history of cancer of the lung, permit treatment with a higher expectation of cure than previously. Studies of fractionation have defined the doses required for control of intrathoracic tumors, and ancillary studies have better defined the treatment volumes necessary. Operable patients benefit from postoperative irradiation only when there is involvement of regional lymph nodes. In inoperable cases, the greatest survival benefit from radiation therapy is found among those who have a high performance status. Patients with adenocarcinoma and large cell carcinoma have a greater probability of long-term survival than those with squamous carcinoma. Investigations of altered fractionation may lead to improved results in radiation therapy for all histopathologic types of carcinoma of the lung.

The role of radiation therapy in the primary management of small cell lung cancer is very much a matter of current debate. Its value in palliative treatment is unquestioned. Disappointment in the apparent inability to demonstrate improvement in survival in some randomized studies as a result of locoregional radiotherapy and prophylactic cranial irradiation may be due to the use of inappropriate study analysis. Recent studies using the end points of 2-year survival and local thoracic control do demonstrate improvements associated with locoregional thoracic radiotherapy. Factors such as total dose and radiation fraction size may be important. Large-field irradiation is also currently attracting interest, but its use should remain a research investigation.

The role of surgical resection in the management of patients with small cell lung cancer remains to be defined. Some data suggest the potential benefit of resection in the few patients with very limited disease (peripheral T1N0 and T2N0 lesions), and there are chemotherapy regimens with 80-85% response rates in patients with more extensive but still localized disease. Interest has been reawakened in the role of adjuvant surgical resection in selected patients by 2 approaches: in patients with peripheral T1 or T2 lesions with negative mediastinal exploration, initial surgical resection followed by an adequate chemotherapeutic regimen and prophylactic cranial irradiation has resulted in an 80% disease-free survival at 30 months; initial chemotherapy in patients with only localized disease is followed by resection in the responders. Approximately 30% of the responders have undergone exploratory thoracotomy after completion of the chemotherapy. Local irradiation, as well as prophylactic cranial irradiation, generally has been used postoperatively. Early pilot studies suggest benefit of this approach in patients found to have T1-3 N0-1 disease but not in those with N2 disease. Prospective, randomized, clinical trials by the Lung Cancer Study Group in North America and its counterparts in Europe are now being carried out in hopes of supplying definitive data relative to this multi-modality therapy in small cell lung cancer. Unfortunately, no data are available to date.

Since the advent of effective cytotoxic combinations in the early 1970s, results from chemotherapy for small cell lung cancer have improved very little. Maintenance chemotherapy appears of no benefit. Although attractive theoretically, "non-cross-resistant" combinations may not yet exist, and most data do not support alternating 1 regimen with another. Anticoagulant therapy with warfarin probably does not have a meaningful impact on survival, at least in extensive stage disease. To date the addition of VP-16, an active new agent, has not produced improvement in survival over earlier programs. The most promising leads to date involve dose escalation, especially with cyclophosphamide. Moderate "outpatient" escalation in limited disease induction therapy produced survival benefit in a randomized trial, and several studies indicate that the incidence of complete response can be increased by more intensive, inpatient "consolidation" with cyclophosphamide with or without other drugs after the induction period. Some form of local therapy, however, will be necessary to control disease in the chest, even with maximal dose intensification.

Advances in the techniques for culturing human tumors in vitro, especially lung cancer cells, have greatly facilitated studies of the biologic properties of both small cell and non-small cell lung cancer cells. Detailed analysis has been done of well-characterized cell lines of both groups with respect to growth properties, biomarker and antigen expression, cytogenetics, and oncogene amplification and expression. Two major conclusions have emerged from these studies: (1) considerable heterogeneity exists within a given tumor type (eg, SCLC) in the expression of a given biomarker, and (2) overlap in the expression of biomarkers exists between cells of SCLC and non-SCLC, suggesting a common stem cell for all types lung cancer. In the future, clinical trials the impact of the biologic properties of cells on responses to therapy and survival will need assessment.

The most examined tumor markers in lung cancer patients are CEA, hormonal peptides, and some neurogenic enzymes in small cell carcinoma. Calcitonin, ACTH, ADH, CEA, neurophysin, oxytocin, beta-endorphin, neuron-specific enolase, and CK BB are elevated in serum specimens in 25-75% of cases of small cell carcinoma. The level of these markers is related to the stage of the disease in groups of patients; elevated pretreatment levels decrease with tumor regression. Marker levels are not valid in defining the tumor load and the presence of disease in the individual patient. It has not yet been documented that the markers can be used for clinical decisions on antineoplastic therapy. A recent development is the finding that measurement of CSF and plasma concentrations of ADH, calcitonin, CK BB, bombesin, and neuron-specific enolase may contribute in the diagnosis of CNS metastases including meningeal carcinomatosis.