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.

What is the meaning of these findings to the practicing chest physician? First, leukotrienes are potent airway constrictors; they are capable of reproducing the type of airway constriction observed in asthma. The role of leukotrienes in this regard has yet to be established, but experiments to test the importance of these agents in this setting are likely to be performed soon. Specifically, several leukotriene receptor antagonists or synthesis inhibitors have been identified and may provide the tools needed to test this crucial hypothesis. Second, the leukotrienes are unique bronchoactive agents in that the degree of hyperresponsiveness between normal and asthmatic subjects varies markedly with the bronchoconstrictor index used to assess response. When one compares normal subjects to asthmatic subjects, there is substantial overlap in leukotriene sensitivity among groups when V30-P is used as the bronchoconstrictor index. However, when the FEV1 is used as the bronchoconstrictor index, there is little overlap in sensitivity between normal and asthmatic subjects, and the separation between the two groups is even more clearly made than it is with histamine or methacholine challenge. Thus, LTD4 inhalation challenge may replace the histamine and methacholine challenges in the diagnosis of cryptic shortness of breath. Third, the differential sensitivity of various bronchoconstrictor indices in both normal and asthmatic subjects when leukotrienes are used may provide clues as to the locus of airway hyperresponsiveness in asthma. Thus, leukotrienes hold the promise of new ways to treat and diagnose asthma, as well as providing new insights into the pathobiology of the disease itself.