Phase I Study of Inhaled Doxorubicin for Patients with Metastatic Tumors to the Lungs

Abstract

Purpose: To evaluate the toxicity profile of inhalational doxorubicin in patients with malignant disease in the lung. Experimental Design:The OncoMyst Model CDD-2a inhalation device aerosolizes compounds to particles of 2 to 3 Am and prevents exhaled aerosol from escaping into the environment. Deposition efficiency of inhaled Technetium 99m was used to predict deposition of doxorubicin and calculate dose. Treatment was repeated every 3 weeks. No more than moderate pulmonary dysfunction was permitted (forced expiratory volume in 1 s, forced vital capacity, and diffusing capacity for carbon monoxide, all >50% predicted; resting SaO 2 >90%).Results: Fifty-three patients were enrolled at 13 dose levels ranging from 0.4 to 9.4 mg/m 2 . The most common histologic diagnoses were sarcoma (n = 19) and non^small cell lung cancer (n = 16). Dose-limiting toxicity (DLT) was observed at the 9.4 mg/m 2 dose level when two of four patients experienced pulmonary DLT. Of 11 patients treated at the 7.5 mg/m 2 dose level, only one showed DLT consisting of a decline in forced vital capacity of >20% from baseline. No significant systemic drug-related toxicity was observed. Several patients experienced declines in pulmonary function test variables, which were attributed to progressive disease. Observed activity included a partial response in a patient with metastatic soft tissue sarcoma previously treated with i.v. doxorubicin and ifosfamide. Conclusions: Inhaled doxorubicin is safe up to a dose of 7.5 mg/m 2 every 3 weeks in patients with cancer who had normal to moderately impaired pulmonary function.Pulmonary metastases commonly occur in solid tumors and are often the predominant or sole site of metastatic involvement. A problem in treating these lesions is the inability to achieve adequate therapeutic concentrations of drugs at the tumor site without suffering substantial systemic toxicity. One approach to improving therapeutic efficacy is targeted dose intensification. This approach has been effectively used in a variety of tumors, including liver, ovarian, and bladder cancer (1 -6), but there is little experience delivering chemotherapeutics directly to the lungs via inhalation (7).Inhalational chemotherapy was first described by Shevchenko and Resnik in 1968. (8). The concept was tested in dogs and subsequently in 58 patients. Antitumor efficacy was observed in 24 patients, but the data are difficult to interpret because of the concurrent use of radiotherapy and less precise methods for response assessment. Tatsumura et al. (9) tested the administration of 5-fluorouracil by inhalation in dogs and found high levels of the drug in the trachea, bronchi, and regional nodes. Subsequently, the same authors treated 10 patients with inoperable lung tumors with 5-fluorouracil via supersonic nebulizer at a dose of 250 mg twice daily for 2 to 3 days per week. There was notable antitumor efficacy, and the therapy was well tolerated. Similar proof-of-principle studies using inhaled doxorubicin or paclitaxel in dogs with macroscopic...

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“…18 Several chemotherapeutic agents have also been tested for aerosol delivery to patients with lung carcinoma, including cisplatin and doxorubicin. [19][20][21][22] Thus, aerosol delivery cationic lipid-encapsulated DNA is a potentially more efficacious approach for the treatment of lung cancer with gene therapy regimens.…”

Aerosolized Medications for Gene and Peptide Therapy

“…Although a number of drugs have been effective in vitro and in animal models, inhalation chemotherapies to treat lung cancer have not progressed beyond phase-1/2 clinical trials in humans due in part to toxicities, poor delivery, and lack of efficacy. [50][51][52][53][54][55] Another development designed to improve delivery of inhaled chemotherapy drugs to the lungs is to formulate them as nanoparticles. 39,40,[47][48] Research is also focusing on liposomal carriers of potent chemotherapy agents such as 9-nitro-camptothecin.…”

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“…In previously published studies, the mass median diameter was required to be #3-5 cm upon diagnosis, otherwise patients were excluded from trials. 29,40,52,53,84,85 Anticancer drugs penetrate normal tissues by both diffusion and convection, 86 with the net flow of fluid from blood vessels balanced by resorption into the lymphatic circulation. Nevertheless, tumors caused by unstructured neoangiogenesis lack functional lymphatics, 87,88 which can lead to increased levels of interstitial fluid pressure in tumors, [89][90][91] which in turn reduces convection and inhibits distribution of macromolecules.…”

“…34 In addition, severe cardiotoxicity was seen in the doxorubicin group. 34, 47 Otterson et al 37,52 created a protocol for inhaled chemotherapy in human subjects, covering all aspects of this treatment modality. Two Phase I and Phase I/II studies demonstrated the adverse effects of aerosol treatment, such as a metallic taste, mild bronchospasm, and moderate reduction of pulmonary function tests.…”