Inhaled Chemotherapy

Introduction

Globally, lung cancer is the most common cause of cancer and is also responsible for the most number of deaths from cancer. ¹ In the United States, lung cancer is estimated to cause over 150,000 deaths annually. ² In the past several years, there have been noteworthy advances in the diagnosis and treatment of patients with lung cancer, but such advances have not translated into significant improvements in the outcomes for patients. There is a critical need for the development of effective and safe treatments that could improve long-term survival for patients with lung cancer.

Lung cancer includes both nonsmall cell lung cancer (NSCLC) and small cell lung cancer (SCLC). The vast majority of the patients are diagnosed with NSCLC and most of studies discussed in this chapter are also focused on patients with NSCLC because SCLC has often spread beyond the lungs at the time of diagnosis. NSCLC is further broadly sub-classified into adenocarcinoma, squamous cell carcinoma, large cell carcinoma and NSCLC not otherwise specified (NOS). In general, the treatment for patients with NSCLC requires a multi-disciplinary approach involving surgery, radiation and systemic chemotherapy. Also disease stage based on TNM classification plays an important role in the selection of treatments. The treatment of patients with early stage disease (stage I and II) is primarily surgical but the role for systemic chemotherapy has been gradually expanding, initially restricted to advanced stage disease, chemotherapy now plays an important role in the treatment of both early stage (stage II disease with positive lymph nodes) and locally advanced NSCLC (stage III). ³ Systemic treatment with cytotoxic chemotherapy is associated with significant adverse effects, and a sizeable proportion of patients may not be candidates for such therapy because of comorbidities and poor performance status. Regional administration of chemotherapy is efficacious for treatment of some solid tumors. With this approach, responses to local treatment are observed even for tumors that have become refractory to systemic chemotherapy.^4,5 The development of novel, local administration of chemotherapy may help to better target the tumor and potentially reduce the occurrence of adverse effects due to systemically administered chemotherapy. Inhaled chemotherapy, therefore, has the potential to become an effective and safe treatment for patients with lung cancer.

Rationale for Inhaled Chemotherapy

Systemic chemotherapy is the primary treatment option for patients with advanced stage lung cancer. However, with systemic chemotherapy, less than 6% of the administered dose is distributed to the lungs, and this may limit the concentrations of chemotherapy that are achieved in the lung. ⁶ The lung weight represents only a very small proportion (∼1.0%) of total body weight), ⁷ so that the total amount of drug required to expose the lungs by inhalation is only a small fraction of that needed to provide the same amount by the oral or parenteral route. Thus, the concentration of chemotherapeutic agents achieved in the lung could be greatly enhanced by inhalation of these agents.^8,9 At present, inhaled chemotherapy is not part of the standard of care for patients with lung cancer, but it provides clinicians with the ability to directly administer chemotherapy to lung tumors.^5,9 Such an approach could be helpful in the regional treatment of both lung cancer and metastasis to the lung. Inhaled chemotherapeutic agents are rapidly absorbed into the systemic circulation because of the large surface area of the alveoli and rich vascular supply, however, the peak blood levels achieved after inhalation are much lower than those after intravenous (IV) administration.^5,6,9,10 Because the inhaled route avoids the effect of first pass metabolism by the liver, inhaled drugs may be effective at lower doses than those employed with systemic chemotherapy.

Inhaled chemotherapy also has the unique ability to target the treatment to a localized region within the lung. Many lung tumors are localized to one lobe or segment of the lung; therefore, selective targeting of tumors could enhance local concentrations within the tumor while avoiding exposure of uninvolved areas of the lung to potentially toxic agents. A variety of approaches have been employed to target tumors with aerosolized agents. Modifications of aerosol droplet size, breathing pattern, depth and duration of breath-hold, timing of the aerosol bolus in relation to inspiratory airflow, and density of the inhaled gas could enhance deposition at specific sites. ¹¹ Newer devices (e.g., the Akita system® or I-neb adaptive aerosol delivery system) are other attractive options for delivery of inhaled anticancer agents because the ability to synchronize aerosol generation with the patient's breathing enhances aerosol delivery efficiency and allows more precise control over the delivered dose. ¹² Enhanced condensational growth is another technique to bypass upper airway deposition and achieve optimal lower respiratory tract deposition. ¹³ The aerosol could also be directed to the diseased area of lung by using an intracorporeal nebulizing catheter (INC) that generates aerosol inside the airway,^9,14 or some molecular or biological recognition that allows the drug to bind to receptors on the surface of the target cells is employed. ¹⁵ An external magnetic field that guides inert superparamagnetic iron oxide nanoparticles (SPIONs) to a desired lung region is another proposed strategy to selectively target lung tumors. ¹⁶

Factors Affecting Drug Delivery

The particle size of the administered anticancer agents plays an important role in their distribution and absorption. Depending on the clinical scenario, the particle size may have to be modified to better target the tumor. For a centrally located tumor, particles with a larger diameter (4–5 pm) are more effective, whereas for more peripheral tumors, aerosolized particles of smaller size (1–3 pm) are needed to achieve a more uniform distribution.^17,18 Aerosol particle size is influenced by airway humidity. The particle can expand in size depending on the humidity level, and this would affect the deposition pattern of the aerosol particles in the respiratory tract. Other physical properties of the aerosol particles, such as pH, electrostatic charge and osmolarity, also play a role in drug delivery. ¹⁹ If the pH and osmolarity are not within the normal range, it can cause irritation of the bronchial mucosa, resulting in cough and bronchoconstriction.

Drug formulation also plays an important role in treatment delivery. Inhaled particles are rapidly cleared in the lung but therapeutic agents encapsulated in lipid bilayers or liposomes could have delayed clearance. This allows the inhaled particles to persist longer and increase drug availability within the lungs. Liposomal formulations also have other advantages including reduced likelihood of irritation to the respiratory tract from the inhaled agents. Inhaled liposomal formulations could also have systemic effects when absorbed through the surface of the respiratory tract. Liposomal formulations of anti-cancer agents are available for systemic administration. So far liposomal cisplatin and 9-nitro camptothecins have been evaluated in humans. Other factors such as inflammation or obstructive airway disease could also affect the distribution of the aerosol particles. Airway obstruction could divert drug delivery to unobstructed airways resulting in a non-uniform deposition of the drug. ²⁰ The obstructed airways may be the areas where the chemotherapeutic agents are needed the most, and aerosol deposition depends on the site of tumor and whether it produces total or partial airway obstruction.^21,22 Moreover, lack of functioning cilia on tumor cells and lower mucociliary clearance rates may allow drugs depositing on the conducting airways in the vicinity of tumors greater opportunity to reach the tumor by direct local penetration. ²³ Furthermore, drugs depositing on the airway mucosal surface are distributed to tumors by a rich plexus of bronchial capillaries that have pre-and post-capillary connections with the pulmonary circulation (Figure 1). ²⁴ As a result, adequate drug concentrations could be achieved even within small tumors that are located in the lung parenchyma and lack direct communication with a major airway. ²⁵ Distribution through the capillary plexus in the airway could also circumvent some of the problems related to direct local penetration or diffusion of drug into the tumor.

OPEN IN VIEWER

FIG. 1.

The bronchial circulation supplies blood flow to the tracheobronchial tree down to the level of the terminal bronchioles as well as to the pulmonary blood vessels, the visceral pleura, hilar lymph nodes, and branches of nerves, including the vagus. A bronchopulmonary anastomosis is shown at right and is enlarged in the inset. Venous drainage is to both the right side of the circulation via the azygos (and hemiazygos) vein and the left side of the circulation via the pulmonary veins. Tumors in the lung receive blood supply from both bronchial and pulmonary vasculature. The major blood supply to bronchial carcinomas is from the bronchial circulation, whereas pulmonary metastases and bronchoalveolar carcinomas receive majority of their blood supply form the pulmonary arteries and veins (Reproduced with permission of the American Thoracic Society. Copyright © 2015 American Thoracic Society, Deffebach ME, Charan NB, Lakshminarayan S, Butler J. The bronchial circulation. Small, but a vital attribute of the lung. Am Rev Respir Dis. 1987 Feb;135(2):463–481). ²⁴

The size of the tumor influences drug absorption. In addition, drugs penetrate into tumors to a variable degree; drugs such as 5-FU that bind macromolecules minimally readily penetrate tumors and have a uniform cytotoxic effect throughout the tumor. ²⁶ In contrast, other drugs such as paclitaxel have a variable penetration into tumors depending on the cellularity of the tumor, density of the interstitial tissues, and apoptotic activity of the drug. ²⁷ Moreover, in normal tissues, the flow of fluid from the blood vessels is balanced by resorption of fluid from the lymphatic circulation. In malignant tumors, disruption of this physiologic balance could increase the interstitial pressure within tumors and thereby alter the absorption and distribution of aerosol chemotherapy. ²⁸

Pharmacokinetics

Pharmacokinetic studies of inhaled chemotherapeutic agents have employed radio-isotope labeled drugs to measure drug absorption and distribution because of inherent difficulties in measuring drug concentrations in lung tissues. In a study comparing IV versus aerosol administration of ¹⁴ C-labeled doxorubicin in dogs, levels of radioactivity achieved in the lungs with aerosol delivery were higher, seemed to persist for longer period of time, and produced significantly lower systemic radioactivity levels than those observed after IV administration. ²⁹

Based on this study, ²⁹ aerosol administration of doxorubicin would be a better option for regional treatment of lung tumors. There are several limitations to this study, ²⁹ including its small sample size, confounded by the presence of inactive drug metabolites that still emit radioactivity, and high levels of radioactivity in the organ may not translate into effective drug penetration into tumor tissue. Despite these drawbacks, the study showed a pharmacokinetic advantage for inhaled over intravenous chemotherapy. ²⁹ Likewise, examination of lung tissue extracts by liquid chromatography identified higher concentrations and slower clearance of paclitaxel in dogs treated with inhaled liposomal paclitaxel versus IV administration of the same drug. ³⁰

Cisplatin administered by an INC to the right caudal lung lobe of healthy dogs produced high platinum concentrations in the lung parenchyma. ⁹ Immediately following a single inhaled dose, mean platinum levels in the lung were 44 times greater than in most other tissues, and blood levels were 15.6 times lower than those observed after intravenous infusion of a comparable dose. ⁹ Later studies with inhaled liposomal cisplatin corroborated these findings. ⁵ Kelsen and colleagues reported that serum levels of cisplatin 5 minutes after an IV dose of 100-120 mg/m², the dose commonly employed for treatment of osteosarcoma, ranged from 1,600 to 9,500 ng/ml (median 5,500 ng/ml). ¹⁰ After 24 hours of IV dosing, the serum cisplatin levels ranged from 400 to 3,500 ng/ml (median 1,400 ng/ml). ¹⁰ High peak levels of cisplatin have been correlated with development of long-term toxicity. ³¹ In contrast, following inhalation of cisplatin, serum levels after 30 minutes ranged from 43.6 to 157.4 ng/ml (median 84.6 ng/ml) and at 18-24 hours post-dose the levels were 47.0 to 153.5 ng/ml (median 81.9 ng/ml). ⁵ As expected, cisplatin levels in the lung after inhalation were much higher than those achieved after IV administration of cisplatin. In 3 patients who had bronchoalveolar lavage (BAL) performed within 24 hours of receiving inhaled lipid cisplatin (ILC), the levels in BAL (9.4, 2,951.9, and 11,201.6 ng/ml) tended to be variable but generally higher than the corresponding levels in serum (61.9, 50.2, and 80.4 ng/ml). ⁵ Likewise, 24 and 96 hours after instillation of cisplatin conjugated with hyaluronan into the lungs of rats, platinum levels in the lung were 5.7-fold and 1.2-fold higher, respectively, compared to rats receiving IV cisplatin. ³² The levels of platinum in the draining lymph nodes were higher and plasma platinum levels were more sustained with a reduced peak plasma concentration after instillation compared to IV administration; however, the animals developed patchy areas of moderate inflammation after instillation, suggesting that aerosolization may be preferable to instillation for delivering such cisplatin conjugates to the lung. ³²

Preclinical Efficacy

The aerosolization process does not affect the cytotoxic effect of the chemotherapy as shown by similar levels of growth inhibition with nebulized and non-nebulized gemcitabine in NCI-H460 and A549 NSCLC cell lines. ³³ In vivo efficacy of aerosol chemotherapy has been evaluated in mouse models for lung metastasis. Mice injected with B16 melanoma cells developed fewer lung metastases when they were treated with inhaled liposomal 9-nitrocamptothecin (L-9NC). ³⁴

Moreover, in nude mice with pulmonary osteosarcoma metastases, treatment with inhaled L-9NC reduced the size of metastatic tumors and prolonged survival. ³⁴ Inhaled gemcitabine also showed treatment efficacy in human LM7 osteosarcoma lung metastasis model. ³⁵ In a similar mouse model given IV injection of LM8 osteosarcoma cells, treatment with aerosol gemcitabine was more effective against lung metastases than intra-peritoneal gemcitabine. ³⁵ In addition, aerosol therapy reduced the number and size of subcutaneous metastases, indicating that aerosol administration had a systemic effect as well. ³⁵ Another mouse model employed intravenous administration of renal carcinoma cells to produce lung metastases (RENCA model). In this model, an aerosolized liposomal formulation of paclitaxel, initiated the day after inoculation of renal carcinoma cells and continued 3 days per week for 2 weeks, reduced the number of visible lung metastases and prolonged survival compared to mice receiving blank liposomes. ³⁰ Another murine model employed intrabronchial implantation of large cell undifferentiated primary lung cancer cells (NCI-H460) in BALB/c nude mice. ³⁶ Weekly inhalation of gemcitabine (8 mg/Kg or 12 mg/Kg), initiated the day after cell implantation and continued for up to 9 weeks, showed complete (in 31% of animals) or partial inhibition of tumor growth compared to mice receiving aerosols of saline. ³⁶

Inhaled paclitaxel and doxorubicin were evaluated in the treatment of dogs with primary lung cancer or lung metastases. ⁴ Treatment resulted in tumor shrinkage in 25% of the dogs, and the adverse effects commonly seen with IV chemotherapy were not seen after inhalation. ⁴

Aerosol administration of gemcitabine to dogs who naturally developed lung metastases from osteosarcoma was well tolerated without significant local or systemic toxicity. ³⁷ Histologically, animals treated with aerosolized gemcitabine showed greater necrosis within tumors, but there were no cures and no prolongation of survival among the treated dogs. ³⁷

While earlier studies demonstrated the feasibility and relative safety of targeted direct local administration of chemotherapeutic agents to the lung, concerns about local toxicity could be reduced by employing formulations designed specifically for inhalation rather than the intravenous formulations of cisplatin and gemcitabine that were employed in the previous investigations.^9,14 Further investigations have been conducted to fulfill the need for formulations that are suitable for inhalation and do not cause local toxicity. For example, Feng and colleagues insufflated freeze-dried porous microspheres of poly(lactic-co-glycolic acid) (PLGA) loaded with doxorubicin and paclitaxel into the lungs of C57BL/6J mice implanted with B16F10 melanoma cells. ³⁸ In this model, the combination of doxorubicin and paclitaxel in the microspheres had a synergistic effect in reducing the number of tumor lesions in the lungs of the mice without causing histological evidence of damage to healthy alveoli. ³⁸ Other novel formulations are also being actively explored to enhance the safety of inhaled chemotherapeutic agents while preserving their efficacy for treating lung cancers.^39,40

Inhaled Chemotherapeutic Agents

Treatment with aerosolized 5-FU, doxorubicin, L-9NC, liposomal paclitaxel and platinum agents has shown activity against lung cancer and metastasis to the lung in preclinical studies. Subsequent phase I trials have assessed the safety and anticancer effect of several chemotherapeutic agents, including inhaled 5-FU, gemcitabine, L-9NC, doxorubicin and platinum agents (Table 1).

Nucleoside Analogs

5-FU is a fluoropyrimidine that acts as an antimetabolite inhibiting deoxyribonucleic acid (DNA) and ribonucleic acid (RNA) synthesis. It is frequently used in the treatment of gastrointestinal malignancies as a single agent or in combination. 5-FU was the first cytotoxic chemotherapeutic agent to be evaluated in an inhaled aerosol form for the treatment of cancer.

Tatsumura and colleagues performed the first study of inhaled chemotherapy in humans. ⁸ This study included pharmacokinetic evaluation of inhaled 5-FU in mongrel dogs. The 5-FU concentrations in the airways and regional lymph nodes were at therapeutic levels whereas only a trace of the drug was detected in the serum. Interestingly, the levels of 5-FU were significantly higher in the tumor tissue than in the normal lung tissue. In addition, metabolic products of 5-FU were detected in the airways and not in the serum, indicating that the drug was primarily metabolized in the lung. ⁸

In the human portion of the study, an initial cohort of 19 patients with resectable lung cancer received inhaled 5-FU two hours prior to surgery. ⁸ Similarly to results in the animal studies, 5-FU concentrations were 5-15 times greater in the resected tumor tissue compared to normal lung. ⁸ A second cohort of 10 patients with previously untreated but unresectable lung cancer were treated with inhaled 5-FU once a day for 2 to 3 times a week. Six patients had a response to therapy with 4 partial responses and 2 patients with complete response. None of these patients had any significant adverse effects from these treatments. ⁸

Gemcitabine is a cytotoxic agent that belongs to the same class of drugs as 5-FU. Intravenous administration of gemcitabine is generally well tolerated and is routinely used in the treatment of several different advanced stage malignancies. In a feasibility study, inhaled gemcitabine, administered once a week for nine weeks, was evaluated in 11 patients with lung cancer. ⁴⁵ A partial response was reported in one patient and stable disease in four patients. ⁴⁵

Doxorubicin

Doxorubicin is an anthracycline that is used in the systemic treatment of a wide variety of malignant tumors. Inhaled doxorubicin has shown preclinical activity against both primary lung cancer and lung metastasis. A phase I trial evaluated the safety of inhaled doxorubicin in patients with metastases to the lung. ⁴³ In this first in human trial, 53 patients with lung metastases were treated with different dose levels of inhaled doxorubicin. Pulmonary toxicities were the most frequently reported adverse events, and five patients had severe adverse effects (> Grade 3).

Partial response was reported in one patient, and stable disease was reported in eight patients.

In a subsequent phase I/II study, patients with treatment-naive advanced stage NSCLC were treated with inhaled doxorubicin along with intravenous cisplatin and docetaxel. ⁴⁴ The maximal tolerated dose (MTD) for inhaled doxorubicin was 6 mg/m². Treatment with this combination was associated with response rate of 29% (7 responders out of 24 evaluable patients) and stable disease rate of 54%. Toxicities were primarily due to systemic chemotherapy, and pulmonary toxicities were generally mild (grade 1-2). In this study, the addition of inhaled doxorubicin to IV chemotherapy did not result in significant improvement in treatment outcomes. The study did not meet the primary objective of overall response rate of > 35%, and the authors did not recommend further evaluation of this combination. ⁴⁴

Liposomal-9-Nitro Camptothecin (L-9NC)

L-9NC is a camptothecin that has shown preclinical activity when administered as aerosol in mice with primary lung cancer and lung metastases. ³⁰ The feasibility and safety of inhaled L-9NC in the treatment of patients with primary lung cancer or metastatic cancer to the lungs was evaluated in a phase I trial. ⁴¹ L-9NC was administered on days 1-5 every week for a period of six weeks. The maximally tolerated dose was 20 pg/kg/day, but L-9NC was well tolerated at a lower dose level of 13.3 pg/kg/day. Two patients with metastatic endometrial cancer had partial response to treatment, and the treatment benefit was not confined to the lung tumors. Treatment response was reported in extrapulmonary sites as well. ⁴¹ L-9NC was detectable in plasma after aerosol administration, and the levels were comparable to those seen after oral administration of the drug. ⁴¹ Overall, inhaled L-9NC was found to be well tolerated with an acceptable safety profile and showed both local and systemic activity against endometrial cancers, but no further clinical development of this formulation has been reported.

Platinum Agents

Platinum agents form the backbone of several combination chemotherapy regimens used in the systemic treatment of lung cancer. Cisplatin and carboplatin are the most common agents used in the treatment of lung cancer.

The safety of inhaled cisplatin was evaluated in a phase I study by Wittgen and colleagues. ⁴² In this study, cisplatin encapsulated in microscopic phospholipid spheres or Sustained Release Lipid Inhalation Targeting (SLIT)^TM cisplatin was administered twice daily in the aerosol formulation to patients with lung cancer or metastatic cancer to the lung. Overall, the treatment was well tolerated, and the serum levels of cisplatin varied between low to undetectable in most cases. No treatment response was reported, but 12 of 17 patients were reported to have stable disease at the time of evaluation. ⁴⁶ Based on this study, inhaled cisplatin was demonstrated to be safe and a potential treatment option for patients with lung cancer. ⁴² Cisplatin lipid complex was also evaluated in the treatment of pediatric patients with pulmonary metastases from recurrent osteosarcoma in a phase I/II study. ⁵ Nineteen patients were enrolled in this study, and they received inhaled cisplatin every 2 weeks. Eleven patients with bulky disease (size of lesions > 2 cm), did not have sustained response, with all of them progressing within 14 weeks. In the eight patients with non-bulky disease (size of lesions < 2 cm), one had partial response and two patients had stable disease. ⁵ Because dose-limiting toxicity was not reported in the clinical trials reported with SLIT^TM,^5,42 further studies would be needed to determine if the efficacy of treatment could be improved with higher doses or use of alternative formulations of cisplatin.

Carboplatin is frequently used in the frontline treatment of advanced stage NSCLC. Inhaled carboplatin in the treatment of NSCLC was evaluated in a small trial. ⁴⁶ In this trial, 60 patients with advanced stage NSCLC were randomized into 3 groups. The first group received IV carboplatin and docetaxel (control arm), whereas the second group received IV docetaxel, two-thirds of the calculated carboplatin IV and one-third carboplatin dose as an inhalant. The third group received the entire dose of carboplatin administered in the aerosol form along with IV docetaxel. Patients receiving both intravenous and inhaled carboplatin (group 2) had better survival outcomes compared to the control arm – 275 days versus 211 days. ⁴⁶ The median overall survival for patients receiving inhaled carboplatin with IV docetaxel was also greater than the control group, but the difference was not statistically significant. Patients receiving carboplatin by inhalation alone had lower plasma levels of the drug compared to the other two groups. ⁴⁶

Development of resistance to chemotherapeutic agents is a frequent cause of treatment failure and tumor recurrence. Several approaches to reduce the development of resistance, such as adding pump and non-pump suppressors to inhaled chemotherapy or combining an active agent with an appropriate drug carrier which can specifically target sites in the respiratory tract where drug transporter genes are highly expressed, or combining inhaled chemotherapy and gene therapy, are currently under investigation.

Side effects of Inhaled Chemotherapy

Despite the potential advantages of inhaled chemotherapy, safety is an important concern that needs to be addressed. Most adverse events of inhaled chemotherapy are due to direct local effects of the chemotherapeutic agents on the upper and lower respiratory tract. Many chemotherapeutic agents are irritants and some agents, such as taxanes, are vesicants, which is the primary reason for administering cytotoxic agents by the IV route. After IV administration, chemotherapeutic agents have the potential to produce a variety of pulmonary toxic effects, including some that are severe and life-threatening. ⁴⁷ Some of these agents, e.g., paclitaxel, gemcitabine, and doxorubicin, could cause acute and chronic pulmonary injury after IV administration. ⁴⁷

Targeted delivery of chemotherapy by INC to a select lung lobe of healthy, anesthetized, mechanically-ventilated dogs was well tolerated and produced no significant clinical, biochemical, or hematological effects.^9,14 Escalating doses of cisplatin (10, 15, 20, 30 mg/m², total inhaled cumulative dose 75 mg/m²) ⁹ or cisplatin (10 mg/m²) combined with escalating doses of gemcitabine (1–6 mg/Kg) ¹⁴ were administered every 2 weeks. Transient radiological changes followed drug administration and histopathologic examination at the end of 10 weeks revealed focal pneumonitis and fibrosis that was confined to a small portion of the select lung lobe.^9,14

A radiographic grading scheme was developed to monitor subclinical toxicity that could help to guide the doses of inhaled chemotherapy. ¹⁴ These studies^9,14 demonstrated the safety and feasibility of giving aerosolized chemotherapeutic agents, alone and in combination, directly into the lungs.

In clinical studies, inhaled chemotherapy appears to be well tolerated and the incidence of extra pulmonary adverse effects such as cytopenias, neuropathy and renal dysfunction are rare when compared to systemic chemotherapy (Table 2). Side effects that have been more commonly observed include fatigue, alteration in taste, glossitis, sore throat, hoarseness, nausea, and vomiting. One patient had a slight reduction in cardiac ejection fraction after inhalation of doxorubicin. ⁴⁴

As expected, the major side-effects of inhaled chemotherapy are related to cough, bronchial irritation, bronchospasm and moderate reduction in pulmonary function tests. Similarly to radiologic changes, pulmonary function tends to show a mild decline after each chemotherapy session, with subsequent gradual improvement. Radiologically, an alveolar interstitial pattern develops with histological findings of moderate fibrosis.^4,9,14,30 Severe pulmonary toxicity has been observed with inhaled doxorubicin, ⁴³ gemcitabine, ⁴⁵ and even with liposomal cisplatin. ⁵ Bronchoconstriction and drop in pulmonary function observed after inhaled chemotherapy could be mitigated by prior administration of inhaled bronchodilators and corticosteroids.^{5,41,43,44,46}

Inhaled chemotherapy also raises certain unique issues such as the risk of inadvertent exposure to caregivers administering the treatment. These issues will have to be closely monitored in future clinical trials. In addition, special precautions are necessary to avoid exposure to the health care workers involved in administering these agents. To minimize occupational exposure of health care workers or others who are administering inhaled chemotherapeutic agents, a well-ventilated room with a HEPA filter air cleaning system for aerosol administration is mandatory. However, Verschraegen and colleagues ⁴¹ evaluated the safety of the formulation and drug delivery system and allowed patients to take their inhaled chemotherapy at home. Establishing the safety of domiciliary chemotherapy could have enormous implications for the convenience and cost of treatment.

Future Perspectives

Over the last few years, rapid advances have been made in the treatment of patients diagnosed with lung cancer. These advances include the development of imaging technologies that allow for more accurate diagnosis and staging, better supportive care for improved symptom management and molecularly targeted therapies. The role for chemotherapy in this shifting paradigm of cancer treatments has not undergone a significant change in the last decade. Inhaled chemotherapy has the potential to change this situation because it offers some distinct advantages over systemic chemotherapy, such as the ability to use lower dose levels and avoid systemic adverse effects. Initial studies have shown that inhaled chemotherapy has activity against lung cancer. Inhaled chemotherapy, if proven to be effective in the treatment of lung cancer, could be a significant addition to the treating physician's armamentarium. But several issues require further clarification before inhaled chemotherapy can be applied in the clinic. The success of inhaled therapy for lung cancer will also depend on the ability to incorporate newer non-cytotoxic treatment options. Immunotherapeutic agents such as monoclonal antibodies, check point inhibitors and adoptive T cell transfer have shown promising activity against solid tumors. Monoclonal antibodies targeting the immune check points PD-1 (programmed cell death-1) receptor and PDL1 (programmed death-ligand) have shown considerable promise in the treatment of advanced stage NSCLC. Several trials are ongoing with these agents and two of them, pembrolizumab and nivolumab are close to receiving approval for the treatment of advanced stage NSCLC.^48,49 It would be of significant interest to see if these agents can be administered as an inhalant and still retain their efficacy.

Inhaled chemotherapy has been primarily evaluated in patients with NSCLC and the role for this treatment modality in patients with small cell lung cancer remains unknown. Evidence of benefit by inhaled chemotherapy would represent a major advance in the treatment of patients with NSCLC.