MTX withdrawal and observation for a short period should be considered in the initial management of patients who develop LPD while on MTX therapy. Responses were consistently observed, but not limited to patients in whom EBV was detected by ISHS or PCR. Further studies are required to confirm these findings and to evaluate the role for EBV in LPD that occur in patients receiving MTX.

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...

Purpose We have shown the feasibility of administering inhaled doxorubicin to patients with cancer. This study evaluated inhaled doxorubicin combined with cisplatin and docetaxel in patients with non–small cell lung cancer. The principal objective was to determine safety and, secondarily, efficacy. Experimental Design Patients who had chemo-naïve advanced non–small cell lung cancer were enrolled in the study. Adequate organ and pulmonary function was required: diffusing capacity for carbon monoxide/forced expiratory volume in 1 second/forced vital capacity ≥50%, resting/exercise O2 saturation ≥90%/85%. In phase I, doxorubicin was escalated: dose level 1 (6 mg/m2) and level 2 (7.5 mg/m2). Escalation was permitted if ≤2 of 6 patients experienced pulmonary dose-limiting toxicity (grade 2 Radiation Therapy Oncology Group lung morbidity; resting O2 saturation of <85%; decrease in diffusing capacity for carbon monoxide, forced vital capacity, or forced expiratory volume in 1 second of ≥20% from baseline or ≤30% of predicted; or grade 3 Common Terminology Criteria for Adverse Events version 3.0 pulmonary toxicity). Doses of cisplatin and docetaxel were 75 mg/m2. Treatments and pulmonary function tests were repeated every 21 days, with up to eight cycles for responding patients. Results Twenty-eight patients were treated at level 1 and eight patients at level 2. Doxorubicin was escalated to 7.5 mg/m2, however, after two patients developed pulmonary dose-limiting toxicity; the remainder were treated at 6.0 mg/m2. Twenty-four evaluable patients received at least two courses or had progressive disease following the first course at the phase II dose. Toxicity was associated with i.v. chemotherapy although one patient had delayed pulmonary toxicity responding to corticosteroids and oxygen. Seven (29%) evaluable patients responded (six partial responses and one complete response) and 13 (54%) patients had stable disease for up to eight cycles. Conclusion Although this combination was safe, the primary objective was not met and will not be pursued further.