**5. Airways delivery of anticancer agents in clinical studies**

#### **5.1 Aerosolisation of anticancer drugs in primary lung cancer 5.1.1 Cisplatin**

Cisplatin is the standard drug for treating non small cell lung cancers. It is given combined with another chemotherapeutic agent. Aerosolised cisplatin was assessed in a phase I study on 17 patients with lung cancer, including 16 with non-small-cell-lung cancer and one with small cell lung cancer (Wittgen et al., 2007). The cancers were progressing despite all previous treatment. Increasing doses of cisplatin encapsulated in liposomes were given. Each aerosol treatment was for 20 minutes with a jet nebuliser. The particles produced had a MMAD of about 3 µm. Each patient was given cisplatin on 1 to 4 consecutive days over a period of 21 days. The initial dose was 24 mg/m², which was doubled to 48 mg/m² without toxicity. The cycle was then shortened from 3 to 2 weeks, and finally to 1 week. Nebulised cisplatin was administered 3 times a day instead of twice. No dose-limiting toxicity was observed and the maximum tolerated dose was not reached. Dyspnea was reported in 11 patients and a productive and irritating cough in 5. Eosinophilia was observed in 4 of these 11 (36.4%) patients. Cisplatin was detected in the blood of only 4 patients. The disease of 12 of the 17 patients became stable and it progressed in five of them, but the study was not constructed to assess the response to treatment. The dose-limiting toxicity was not reached, precluding a phase II study.

#### **5.1.2 Doxorubicin**

#### **5.1.2.1 Safety and pharmacokinetic data**

Anthracycline is usually administered intravenously to treat various cancers, including small cell lung cancer. The most severe adverse response is cardiac toxicity. Delivering the drug by inhalation is an interesting alternative route which may limit the cardiac toxicity. A phase I study was conducted by Otterson et al. to assess the safety of inhaled doxorubicin (Otterson et al., 2007). The 53 patients taking part included 16 patients with a primary lung tumour without histology details. The remaining 37 had pulmonary metastases of sarcoma (n=19), osteosarcoma (n=6), colorectal (n=4), thyroid (n=3) and other primary tumours (n=5). They were given doxorubicin with a pneumatic nebuliser fitted with a device that captured any fugitive aerosol to protect health worker. The starting dose was 0.4 mg/m². Inhalation was given every 3 weeks. The majority of adverse events were pulmonary with cough (n=27), dyspnea (n=9), chest pain (n=5), wheezing (n=4), hoarseness (n=3), hemoptysis (n=1), and bronchospasm (n = 1). While 5 patients suffered grade 3-4 pulmonary toxicity such as hypoxemia or decreased lung function tests, it was difficult to differentiate the adverse effects of treatment and the consequences of the pulmonary disease. Two patients suffered severe toxicity in response to a dose of 9.4 mg/m², with respiratory distress in 1 patient and bilateral ground glass infiltrates in the other. The lung function tests

The Airways: A Promising Route for the Pulmonary Delivery of Anticancer Agents 65

days a week every 3 weeks. The histology of the lung tumours was not specified, neither were any details about the nebulisation procedure given, except that an air flow of 10 liters per minute was used to generate the aerosol. No toxicity up to grade 2 was observed. The maximum drug concentration was seen 2 hours at the end of the aerosolisation, which

The same group then carried out a phase I study with nebulised L9-NC to determine the dose-limiting toxicity (Verschraegen et al., 2004). L9-NC was aerosolised with a pneumatic nebuliser with an air flow of 10 liters per minute and a mouth breathing-only face mask. Patients were treated for 5 days a week as above. The dose was increased by reducing the interval between treatments or increasing the concentration of L9-NC. The patients were premedicated with an inhaled bronchodilatator and steroids after one of them developed a grade 2 bronchial irritation. The starting dose was 6.7 µg/kg. All 25 patients completed the protocol except one who could not undergo nebulisation because of claustrophobia. The 26.6 µg/kg dose was poorly tolerated, with pharyngeal mucositis. The 20.0 µg/kg dose 2 patients to develop grade 3 asthenia but the 13.3 µg/kg treatment was well tolerated. There were mild side effects, such as a cough in 67% of patients, bronchial irritation in 46%, sore throat in 33%, nausea in 62%, vomiting in 33%, fatigue in 50%, anemia and neutropenia in 29%, and skin rash around the face mask in 21%. There was a 20% decrease in FEV1 during treatment which rapidly returned to baseline. Other lung function parameters were stable. The blood plasma L9-NC concentration peaked 2 hours after nebulisation, which was followed by a sustained decrease. The blood concentrations were similar to those obtained after oral administration, without any haematological toxicity. The responses to treatment were reported, but a phase I study is not designed to do so. Two patients had a partial remission, with endometrial carcinoma metastatic to the lungs only, but they suffered a relapse within 8 and 3 years respectively. One of these patients had a partial response of hepatic metastasis. The disease of the patients with lung tumours (3 of 6) was stabilized. Thus, nebulised L9-NC seems to be promising for treating pulmonary metastases rather than primary lung tumours. The recommended phase II study dose was 13.3 µg/kg 5 days a

Tastumura et al. were the first to report chemotherapeutic nebulisation for cancer patients (Tatsumura et al., 1983). They treated six patients with lung cancer with 5-FU aerosolised with an ultrasonic nebuliser. Two of them had complete responses and two others partial responses. Only traces of 5-FU were detected in the blood. These encouraging results led to another clinical trial to assess nebulised 5-FU for treating primary lung tumour patients (Tatsumura et al., 1993). A first group of 19 patients with resectable lung cancer was given nebulised 5-FU, 2 hours before surgery to determine the 5-FU concentrations in excised lung tissue. The 5-FU concentration in the tumour tissue was 5-15 times higher than in the normal lung tissue (p<0.05). The 5-FU concentrations were higher in proximal tissue and regional lymph nodes than in the remaining tissue. No drug was detected in blood samples. A second group of ten patients with unresectable lung cancer (6 squamous cell carcinomas and 4 adenocarcinomas) were given inhaled 5-FU twice a day for 3 days per week to evaluate their response to treatment. Of these, 6 had objective responses, including two complete responses and four partial responses. The disease of the remaining four patients was unchanged and 3 of them died of their disease. No toxicity was detected. Despite these

rapidly decreased. The disease of two patients stabilized.

week every week.

**5.1.4 5-Fluorouracile** 

of the whole population were relatively stable and there was little non-pulmonary toxicity. There was no evidence of hematological toxicity. The authors concluded that the recommended dose for a phase II study is 7.5 mg/m². The maximal concentration (Cmax) of doxorubicin in the blood was low when the dose was less than 3 mg/m². Cmax increased 1.6 times with doses of 3.8 - 7.5 mg/m². Cmax was more than doubled with doses of from 7.5 to 9.4 mg/m². The maximal doxorubicin peak in the blood occurred within 5 minutes. This was due to its rapid passage through the alveolar-capillary barrier because doxorubicin is small and lipophilic.

One patient with spindle cell sarcoma gave a partial response, while the diseases of 8 patients were stable after 5 courses: 2 with bronchoalveolar carcinoma, 2 with soft tissue sarcoma, 1 with endometrial carcinoma, and 3 with thyroid cancer. The diseases of 6 patients became stable after three courses. Two patients stopped treatment after first administration. The diseases of the remaining patients progressed.

Very little inhaled doxorubicin enters the blood and probably has little systemic toxicity. It is difficult to come to any conclusion about treatment efficacy because the study was not constructed to do so, and the histological subtypes of cancers varied greatly. However, the stabilized bronchioalveolar carcinoma cases suggest that this histological pattern might be suitable for inhalation treatment with doxorubicin.

#### **5.1.2.2 Efficacy data**

Inhaled doxorubicin associated with systemic cisplatin and docetaxel at 75 mg/m² was tested in a phase I/II study on chemo-naive patients with advanced NSCLC (Otterson et al., 2010). Among the 36 patients included in the study, 28 were given dose 1 (6 mg/m²) and 8 were given dose 2 (7.5 mg/m²). The diffusing capacity of the lung for carbon monoxide (DLCO) of two of the patients given 7.5 mg/m² decreased and the recommended dose for the phase II study was 6 mg/m². The 34 patients in the phase II study, included 16 (47.1%) with adenocarcinoma, 5 (14.7%) with squamous cell carcinoma, 1 (2.9%), with large cell carcinoma, 11 (32.4%) with unspecified histology and 1 (2.9%) with a mixed tumour (squamous and adenocarcinoma). The patients were given 1 to 8 treatment cycles. Seven patients were given only one cycle and left the study because their disease progressed (n=3), adverse event (n=2), withdrawal of consent (n=1) or the physician's decision (n=1). There was little pulmonary toxicity except that the lung function of 5 patients decreased, but they did not stop their treatment. Among patients, 24 were evaluable, including 6 (25%) with a partial response and 1 (4%) with a complete response. The remaining 17 patients included 13 (54%) whose disease was stable and 4 (17%) whose disease progressed. Response rate was poorer than expected by the authors (at least 9 responding patients). The median overall survival time was 14.4 months for those given the level 1 dose and 19.5 months for those given the level 2 dose with no statistical difference. The median overall survival time was longer than is usually observed in clinical trials of lung cancer treatment. This discrepancy may be due to bias associated with the selection of the patients or because inhaled doxorubicin plus platinum chemotherapy really had some effect. A phase III study is expected to determine which of these hypotheses is correct.

#### **5.1.3 Campthotecin**

Vershraegen et al. **e**xamined the feasibility of using aerosolised liposomal 9-nitro-20(S) camptothecin (L9-NC) (Verschraegen et al., 2000). They treated 6 patients with primary or secondary lung tumours who had not responded to previous treatment with L9-NC for 5 days a week every 3 weeks. The histology of the lung tumours was not specified, neither were any details about the nebulisation procedure given, except that an air flow of 10 liters per minute was used to generate the aerosol. No toxicity up to grade 2 was observed. The maximum drug concentration was seen 2 hours at the end of the aerosolisation, which rapidly decreased. The disease of two patients stabilized.

The same group then carried out a phase I study with nebulised L9-NC to determine the dose-limiting toxicity (Verschraegen et al., 2004). L9-NC was aerosolised with a pneumatic nebuliser with an air flow of 10 liters per minute and a mouth breathing-only face mask. Patients were treated for 5 days a week as above. The dose was increased by reducing the interval between treatments or increasing the concentration of L9-NC. The patients were premedicated with an inhaled bronchodilatator and steroids after one of them developed a grade 2 bronchial irritation. The starting dose was 6.7 µg/kg. All 25 patients completed the protocol except one who could not undergo nebulisation because of claustrophobia. The 26.6 µg/kg dose was poorly tolerated, with pharyngeal mucositis. The 20.0 µg/kg dose 2 patients to develop grade 3 asthenia but the 13.3 µg/kg treatment was well tolerated. There were mild side effects, such as a cough in 67% of patients, bronchial irritation in 46%, sore throat in 33%, nausea in 62%, vomiting in 33%, fatigue in 50%, anemia and neutropenia in 29%, and skin rash around the face mask in 21%. There was a 20% decrease in FEV1 during treatment which rapidly returned to baseline. Other lung function parameters were stable. The blood plasma L9-NC concentration peaked 2 hours after nebulisation, which was followed by a sustained decrease. The blood concentrations were similar to those obtained after oral administration, without any haematological toxicity. The responses to treatment were reported, but a phase I study is not designed to do so. Two patients had a partial remission, with endometrial carcinoma metastatic to the lungs only, but they suffered a relapse within 8 and 3 years respectively. One of these patients had a partial response of hepatic metastasis. The disease of the patients with lung tumours (3 of 6) was stabilized. Thus, nebulised L9-NC seems to be promising for treating pulmonary metastases rather than primary lung tumours. The recommended phase II study dose was 13.3 µg/kg 5 days a week every week.

#### **5.1.4 5-Fluorouracile**

64 Advances in Cancer Therapy

of the whole population were relatively stable and there was little non-pulmonary toxicity. There was no evidence of hematological toxicity. The authors concluded that the recommended dose for a phase II study is 7.5 mg/m². The maximal concentration (Cmax) of doxorubicin in the blood was low when the dose was less than 3 mg/m². Cmax increased 1.6 times with doses of 3.8 - 7.5 mg/m². Cmax was more than doubled with doses of from 7.5 to 9.4 mg/m². The maximal doxorubicin peak in the blood occurred within 5 minutes. This was due to its rapid passage through the alveolar-capillary barrier because doxorubicin is small

One patient with spindle cell sarcoma gave a partial response, while the diseases of 8 patients were stable after 5 courses: 2 with bronchoalveolar carcinoma, 2 with soft tissue sarcoma, 1 with endometrial carcinoma, and 3 with thyroid cancer. The diseases of 6 patients became stable after three courses. Two patients stopped treatment after first

Very little inhaled doxorubicin enters the blood and probably has little systemic toxicity. It is difficult to come to any conclusion about treatment efficacy because the study was not constructed to do so, and the histological subtypes of cancers varied greatly. However, the stabilized bronchioalveolar carcinoma cases suggest that this histological pattern might be

Inhaled doxorubicin associated with systemic cisplatin and docetaxel at 75 mg/m² was tested in a phase I/II study on chemo-naive patients with advanced NSCLC (Otterson et al., 2010). Among the 36 patients included in the study, 28 were given dose 1 (6 mg/m²) and 8 were given dose 2 (7.5 mg/m²). The diffusing capacity of the lung for carbon monoxide (DLCO) of two of the patients given 7.5 mg/m² decreased and the recommended dose for the phase II study was 6 mg/m². The 34 patients in the phase II study, included 16 (47.1%) with adenocarcinoma, 5 (14.7%) with squamous cell carcinoma, 1 (2.9%), with large cell carcinoma, 11 (32.4%) with unspecified histology and 1 (2.9%) with a mixed tumour (squamous and adenocarcinoma). The patients were given 1 to 8 treatment cycles. Seven patients were given only one cycle and left the study because their disease progressed (n=3), adverse event (n=2), withdrawal of consent (n=1) or the physician's decision (n=1). There was little pulmonary toxicity except that the lung function of 5 patients decreased, but they did not stop their treatment. Among patients, 24 were evaluable, including 6 (25%) with a partial response and 1 (4%) with a complete response. The remaining 17 patients included 13 (54%) whose disease was stable and 4 (17%) whose disease progressed. Response rate was poorer than expected by the authors (at least 9 responding patients). The median overall survival time was 14.4 months for those given the level 1 dose and 19.5 months for those given the level 2 dose with no statistical difference. The median overall survival time was longer than is usually observed in clinical trials of lung cancer treatment. This discrepancy may be due to bias associated with the selection of the patients or because inhaled doxorubicin plus platinum chemotherapy really had some effect. A phase III study

Vershraegen et al. **e**xamined the feasibility of using aerosolised liposomal 9-nitro-20(S) camptothecin (L9-NC) (Verschraegen et al., 2000). They treated 6 patients with primary or secondary lung tumours who had not responded to previous treatment with L9-NC for 5

administration. The diseases of the remaining patients progressed.

is expected to determine which of these hypotheses is correct.

suitable for inhalation treatment with doxorubicin.

and lipophilic.

**5.1.2.2 Efficacy data** 

**5.1.3 Campthotecin** 

Tastumura et al. were the first to report chemotherapeutic nebulisation for cancer patients (Tatsumura et al., 1983). They treated six patients with lung cancer with 5-FU aerosolised with an ultrasonic nebuliser. Two of them had complete responses and two others partial responses. Only traces of 5-FU were detected in the blood. These encouraging results led to another clinical trial to assess nebulised 5-FU for treating primary lung tumour patients (Tatsumura et al., 1993). A first group of 19 patients with resectable lung cancer was given nebulised 5-FU, 2 hours before surgery to determine the 5-FU concentrations in excised lung tissue. The 5-FU concentration in the tumour tissue was 5-15 times higher than in the normal lung tissue (p<0.05). The 5-FU concentrations were higher in proximal tissue and regional lymph nodes than in the remaining tissue. No drug was detected in blood samples. A second group of ten patients with unresectable lung cancer (6 squamous cell carcinomas and 4 adenocarcinomas) were given inhaled 5-FU twice a day for 3 days per week to evaluate their response to treatment. Of these, 6 had objective responses, including two complete responses and four partial responses. The disease of the remaining four patients was unchanged and 3 of them died of their disease. No toxicity was detected. Despite these

The Airways: A Promising Route for the Pulmonary Delivery of Anticancer Agents 67

with a low dose given subcutaneously IL-2 (33%), or with low-dose systemic IL-2 and interferon-alpha (56%). The overall response rate was 16% for IL-2 alone, 49% for IL-2 plus subcutaneous (s.c.) IL-2, and 35% for IL-2 plus s.c. IL-2 and interferon. The median overall response was 9.6 months. The pulmonary metastases of 15% of patients progressed and those of 55% were stabilized. The authors identified risk factors of poor response in patients treated with inhaled IL-2 (Huland et al., 1999b). Of the 116 patients given inhaled IL-2 (natural or recombinant), 86 had a poor response and at least one of the following risk factors: 1 metastatic location (86%), interval between diagnosis and treatment of <12 months (62%), weight loss prior to therapy (41%), and ECOG (Eastern Cooperative Oncology Group) performance status ≥2 (13%). However, the response rate, including long-term stabilization, was 27 to 57% in patients with these risk factors. Inhaled IL-2 should be proposed for all renal cancer patients with pulmonary metastases. However, patient with multiple nodules and who are tired may have reduced lung deposition of inhaled treatment. Another clinical trial was conducted on 40 patients with progressive pulmonary metastases of a renal cell carcinoma. They were treated with inhaled IL-2 3 times a day for a total dose of 18 million units (MU) plus a low dose of systemic IL-2 (Merimsky et al., 2004). The dose was reduced for one patient because of a cough and dyspnea. The dose was increased to 36 MU for seven patients whose disease progressed. The response rate was poorer than in previous studies supervised by Huland et al. Only one of the 40 patients had a partial response, but the disease of 22 patients was stabilized. The median time to progression was 8.7 months. Toxicity was low including cough, weakness, dyspnea, fever and abdominal pain. The efficacy and safety of inhaled IL-2 were also assessed in a retrospective study on 51 patients with pulmonary metastases of renal cell carcinoma (Esteban-González et al., 2007). The patients were given 3 cycles of 36 MU per day for 5 days per week for 12 weeks. Toxicity was low, always grade 1 or 2. Cough and fatigue were the most common problems. The overall objective response rate was 13.7%. The median progression-free survival time was 8.6 months and the overall survival time was 23 months. Inhaled IL-2 seemed to have an effect but it was not compared to a control group. A retrospective study compared 94 patients with metastases of renal carcinoma treated with inhaled IL-2 to 103 patients treated with systemic IL-2 (Huland et al., 2003). The toxicity in the two groups was radically different. Cough was observed in the inhaled IL-2 group and fever, fatigue, skin lesion in systemic IL-2 group. The 1-, 2- and 3-year survival rates were estimated to be 47%, 28% and 23% for inhaled IL-2 and 26%, 10% and 1% for the systemic IL-2 group. The hazard ratio for inhaled IL-2 was 0.435. The death risk of patients treated with inhaled IL-2 was decreased by

The largest clinical trial with a drug delivered *via* the pulmonary route to treat lung cancer was the study conducting by Atzpodien et al. (Atzpodien et al., 2006). The 379 patients with metastases of renal cell carcinoma were randomly assigned to group I (143 patients) or group II (236 patients). The group I patients in arm A were given subcutaneous IL-2, subcutaneous interferon-α plus 13-cis-retinoic acid; those in arm B were given the same treatment as arm A plus inhaled IL-2. The patients in group II were assigned to arm C (arm A plus intraveinous 5-FU) or arm D (arm A plus oral capecitabine). The 13-cis-retinoic acid used in this study is a regulator of cell differentiation that has been reported to enhance the antitumor effect of IL-2/IFN-α on renal cell carcinoma metastases (Atzpodien et al, 1995). Patients with pulmonary metastases were preferentially assigned to group I. Arm B patients were given systemic IL-2 and IFN- plus inhaled IL-2 on days 1 to 5 of weeks 2 and 3 and

44%.

promising results, no clinical trial to assess the efficacy of inhaled 5-FU has been published, probably because i.v. injected 5-FU is not indicated for treating lung cancer.

#### **5.1.5 Non-steroidal anti-inflammatory drugs**

To the best of our knowledge, no clinical trial has assessed the efficacy of inhaled nonsteroidal anti-inflammatory drugs for treating cancer patients, although aerosolised celecoxib plus i.v. chemotherapeutic agents showed good results in preclinical studies.
