Selective Pulmonary Artery Perfusion with carboplatin for the treatment of NSCLC: a phase I trial

Cancer is the leading cause of death before the age of 85 years resulting in
more than half a million deaths per year in the United States [ref 1 of the
protocol, page 22]. In 2005, primary lung cancer was the second leading cancer
type in the United States with approximately 190,000 new cases to be estimated
for 2006. Among all cancer types, lung cancer has the highest death rate [2].
Lung cancer is usually treated by surgical resection and/or cytostatic drug
administration depending on the disease stage. Stage I (a and b) and II NSCLC
are currently treated by surgical resection and (neo-)adjuvant cytostatic
therapy resulting in a 5-year survival of 75, 60 and 40% respectively [3].
However, adjuvant intravenous chemotherapy results in a 5-year survival benefit
of 4-12% in patients eligible for surgery.
Patients suffering from stage IIIa and b NSCLC are treated intravenously using
gemcitabine and a platin-derivate, e.g. cisplatin or carboplatin, resulting in
an overall response of 40% and a 5-year survival of 20% [3]. However, infusion
of carboplatin is dose-limited due to the presence of bone marrow suppression
at higher doses and renal dysfunction.
Therefore, selective pulmonary artery perfusion (SPAP) has been developed as a
new method of cytostatic drug delivery to the lungs for the treatment of lung
cancer in order to achieve more effective down-staging of the tumour (T) and
lymph node (N) status. Concomitantly, lung cancer is a systemic disease and
therefore SPAP aims to achieve serum concentrations that are equivalent
compared to intravenous administration [6-8].

To determine toxicity of selective pulmonary artery perfusion (SPAP) for the
treatment of non small cell lung cancer.

Phase 1, 4 levels:

Level 1 (n=3)
Cyclus 1 (3 weeks):
Day 1: gemcitabine (1250 mg/m2) and carboplatin (AUC 6) iv
Day 8: gemcitabine iv (1250 mg/m2)
Cyclus 2 (3 weeks): Day 1: gemcitabine iv (1250 mg/m2) and carboplatin SPAP
(AUC 6, 15 minutes without BFO)
Day 8: gemcitabine iv (1250 mg/m2)
Restaging (at 8 weeks): CT, EUS, PET, V/Q, Lung function/DLCO, bronchoscopy
Surgery or radiotherapy
Toxicity determination (at 15 weeks): HRCT, Lung function/DLCO

Level 2 (n=3)
Cyclus 1 (3 weeks):
Day 1: gemcitabine (1250 mg/m2) and carboplatin (AUC 6) iv
Day 8: gemcitabine iv (1250 mg/m2)
Cyclus 2 (3 weeks): Day 1: gemcitabine iv (1250 mg/m2) and carboplatin SPAP
(AUC 6, 15 minutes and 10 min. BFO)
Day 8: gemcitabine iv (1250 mg/m2)
Restaging (at 8 weeks): CT, EUS, PET, V/Q, Lung function/DLCO, bronchoscopy
Surgery or radiotherapy
Toxicity determination (at 15 weeks): HRCT, Lung function/DLCO

Level 3 (n=3)
Cyclus 1 (3 weeks):
Day 1: gemcitabine (1250 mg/m2) and carboplatin (AUC 6) iv
Day 8: gemcitabine iv (1250 mg/m2)
Cyclus 2 (3 weeks): Day 1: gemcitabine iv (1250 mg/m2) and carboplatin SPAP
(AUC 6, 15 minutes and 20 min. BFO)
Day 8: gemcitabine iv (1250 mg/m2)
Restaging (at 8 weeks): CT, EUS, PET, V/Q, Lung function/DLCO, bronchoscopy
Surgery or radiotherapy
Toxicity determination (at 15 weeks): HRCT, Lung function/DLCO

Level 4 (n=3)
Cyclus 1 (3 weeks):
Day 1: gemcitabine (1250 mg/m2)and carboplatin (AUC 6) iv
Day 8: gemcitabine iv (1250 mg/m2)
Cyclus 2 (3 weeks): Day 1: gemcitabine iv (1250 mg/m2)and carboplatin SPAP (AUC
6, 15 minutes and 30 min. BFO)
Day 8: gemcitabine iv (1250 mg/m2)
Restaging (at 8 weeks): CT, EUS, PET, V/Q, Lung function/DLCO, bronchoscopy
Surgery or radiotherapy
Toxicity determination (at 15 weeks): HRCT, Lung function/DLCO

NB:
1. Gemcitabine 1250 mg/m2 i.v.: gemcitabine will be added to 250 mL of NaCl
0.9% and administered according to the current standard treatment protocol.
2. Carboplatin (AUC 6) i.v.: carboplatin will be added to 500 mL of glucose 5%
and administered according to the current standard treatment protocol.
3. Carboplatin (AUC 6) SPAP: carboplatin will be added to 250 mL of glucose 5%
and administered in 15 minutes according the technique as described in the
introduction.

Insertion of a balloon catheter into the left or right pulmonary artery after
venous puncture in the groin. After insertion, the drug is infused; depending
on the group, a balloon will be inflated after infusion during 10, 20 or 30
minutes; after infusion and/or balloon inflation, the catheter will be removed
immediately.

A Medline search revealed two human studies evaluating pulmonary artery
infusion of cisplatin (60 and 30 mg/m2), mitomycin (10 mg/m2) combined with
navelbine (25 mg/m2) and one study evaluating doxorubicin (10-20 mg) [ref 9-11
protocol, page 22]. In total, 177 procedures are described in 74 patients.
Pulmonary toxicity like pneumonitis or pulmonary fibrosis is not described.
Regarding the lack of pulmonary toxicity, it is important to emphasize that
pulmonary artery infusion was performed in lobar or segmental arteries which is
in contrast to our studies in which infusion occurred centrally, proximal of
the first side branches. The pulmonary distribution volume in our studies will
be therefore larger than in the described studies in the literature suggesting
that they even had higher lung concentrations than we will have.
Furthermore, no significant histological toxicity was observed in our own
animal studies [6-11].