Inhalation Therapy for Lung Cancer ‘Primed for Growth,’ Investigator Says

NEW YORK-Inhalation therapy for lung cancer, explored for more than a decade, "is now primed for growth," according to Roman Perez-Soler, MD. "There's a strong rationale for use of inhaled therapy in certain forms of lung cancer and lung premalignancy," he said. "And there's preliminary evidence of technical feasibility and clinical activity; it's probably still anecdotal, but there are several trials all reporting some type of response." Dr. Perez-Soler, professor of medicine and chairman and director of medical oncology, Montefiore Medical Center/Albert Einstein College of Medicine, Bronx, New York, has over 20 years' research experience in liposomal drug delivery. He spoke about the current state of investigation into inhaled liposomal therapy for lung cancer at the 10th International Conference on Screening for Lung Cancer, hosted by Weill Medical College of Cornell University. During the 10- to 25-year gestation period of lung cancer, he noted, the bronchial epithelium is attacked by inhaled carcinogens causing sequential histological damage also associated with specific genetic molecular abnormalities. "As the lesions become detectable in increasingly smaller sizes, it makes sense to think that maybe we can intervene directly with an inhaled therapeutic agent," Dr. Perez-Soler said. Increasingly, he said, clinicians are seeing bronchoalveolar carcinoma, "an enigmatic form of lung cancer" that tends to be multifocal, multinodular, and with tiny bilateral lesions that are detected relatively early. Because of the size of the lesions, inhaled treatment could be more effective and perhaps prevent disease progression. In bronchoalveolar cancer, Dr. Perez-Soler explained, while the surface of the alveoli is malignant, the cells do not tend to grow and coalesce into a solid mass. Because the lesions are not very thick, multiple inhalation treatments could result in a "peeling off" of the lesion. The inhalation mode is expected to be more effective than systemic therapy through the capillaries, where the drug has to diffuse through the vessels to the surface of the epithelium. The inhalation therapy benefit of direct drug delivery to the bronchoalveolar epithelium and lung parenchyma is well known; experiments have shown that only about 1% of an intravenously injected dose reaches the lung parenchyma vs 15% to 20% when the drug is administered via a regular nebulizer, he said. Another benefit is the reduced toxicity that comes with reduced systemic distribution. A third potential advantage of inhalation therapy is the possible preferential delivery of the agent to the regional lymphatic system. Variety of Agents Tested Over the past 10 years, mostly in small studies of lung and other cancers, Dr. Perez-Soler said, inhaled therapy has been tested using a variety of cytotoxic agents, including fluorouracil(Drug information on fluorouracil), doxorubicin(Drug information on doxorubicin), cisplatin(Drug information on cisplatin) (Platinol), and paclitaxel(Drug information on paclitaxel). In almost all of those studies, responses were reported. Differentiating agents have also been studied as inhaled therapy in lung cancer, and at least seven have shown clinical activity: interleukin-2, interferon, GM-CSF, hypomethylating agents, cyclo-oxygenase-2 (COX-2) inhibitors, epithelial growth factor receptor (EGFR) inhibitors, and proteasome inhibitors. Dr. Perez-Soler and his colleagues have worked with biotechnology researchers at Transave Inc. (Monmouth Junction, New Jersey) over the last few years, to optimize inhalation therapeutics for lung cancer. Together, they developed Sustained release Lipid Inhalation Targeting technology, or SLIT, to improve current injectable or inhaled products by producing a targeted, prolonged therapeutic effect in the lung that reduces systemic and local toxicity, and permits dose reduction. Transave has sponsored a phase I study of SLIT with cisplatin, conducted by Pieter E. Postmus, MD, PhD, of the Department of Pulmonology, Free University Hospital, Amsterdam, Netherlands. So far, Dr. Postmus has been able to escalate to an inhaled liposomal cisplatin dose of 48 mg/m² every 2 weeks or 24 mg/m² every week, similar to intravenous doses, without reaching dose-limiting toxicity. "There has been some nausea and vomiting, but basically cisplatin can be given easily by inhalation without causing any irritation," Dr. Perez- Soler said. In about 50% of lung cancers and 15% of severe dysplasias, p53 function is lost because of a mutation; if p53 function can be restored in those lesions, apoptosis can be induced. Dr.Perez-Soler and his coworkers expect to initiate a study of inhaled p53 in a liposome carrier later this year. Prior similar work includes that of David Carbone, MD, of Vanderbilt-Ingram Cancer Center, in which p53 was administered in adenovirus intra-bronchially and well-tolerated in patients with bronchoalveolar carcinoma. Dr. Perez-Soler's team assessed the effects of direct intratracheal administration of the p53 gene in a cationic lipid vector in a mouse model of lung cancer. Treatment was given on days 4, 8, 12, 16, and 20. Histological analysis of animals sacrificed approximately 6 weeks after the start of treatment showed that liposomal p53 gene therapy had prevented tumor growth in the lung bilaterally and led to longer survival, compared with controls. The investigators confirmed these results using the same formulation as inhaled therapy. They have finished preclinical toxicology studies of this cationic lipid polymer p53 gene therapy and expect to initiate further studies at Albert Einstein College of Medicine in the second half of 2004. "Inhalatory therapies for lung cancer are still a relatively new field," he concluded. "There is a lot of work to be done, basically optimizing the agents; selecting the correct agent; and selecting the right delivery system, dose, schedule, and nebulizer, before we can embark on comparative efficacy studies."