State of the Art - Cleveland Clinic

State of the Art 1187
(PDT) under local anesthesia and sedation. PDT is approved tumoral microvessel density (IMD) has also been variably re-
by the U.S. Food and Drug Administration for the endobronchial lated to a poorer prognosis (308). Levels of cellular expression of
treatment of microinvasive NSCLC and for palliation in patients VEGF (309–314) and its receptor (VEGFR), the EGF receptors
with obstructing tumors. A mixture of different porphyrin-based (EGFR/HER-1/c-Erb-B1 [315–318] and HER-2/c-Erb-B2 [315–
oligomers (such as Photofrin [porfimer sodium]) is injected intra- 318]), and MMP-9 (317) have all been found to be increased in
venously, with care not to extravasate. The drug is cleared in certain lung cancers, although how this relates to prognosis is
72 hours, but is retained for up to 30 days in tumors, skin, liver, still contentious (310–316, 319, 320).
and spleen. After 48 hours light with a wavelength of 630 nm At present many candidate molecules have been developed
is shone from a laser onto the tumor and the resulting phototoxic to inhibit angiogenic pathways in the hope of making an impact
reaction destroys tumor to a depth of 5 to 10 mm. The light is in cancer treatment, and this review considers those molecules
delivered though a cylindrical diffuser fiber that is passed through that have reached Phase III trials.
the working channel of the flexible bronchoscope and the tip is The growth factors and their receptors are judged to have
then embedded into the lesion. The bronchoscopy should be enormous potential as novel therapeutic targets. A Phase II trial
repeated at 48 hours to clear debris and secretions and prevent of a recombinant humanized anti-VEGF antibody (rhuMAbcompromise
of the airway (a particular problem when treating VEGF, Bevacizumab; Genentech, San Francisco, CA) in combi-
tracheal lesions, and those requiring high energy levels). Another nation with paclitaxel and carboplatin in NSCLC was sufficiently
complication of PDT is skin photosensitivity. Patients are kept encouraging that a large Phase III trial involving metastatic
in special hospital rooms and are given advice before discharge NSCLC is underway. Even more hope has been invested in the
such as to avoid even normal daylight for 4–6 weeks after the EGFR-blocking agents. The most extensively studied of these
injection. Care should be taken when using pulse oximeters, agents are (1) monoclonal antibodies against the extracellular
which have caused severe finger-tip burns for monitoring pa- domain of the receptor, including IMC-C225 (Erbitux; ImClone
tients during the procedure. PDT has been used to treat early Systems, Somerville, NJ) directed against the EGFR and trastulung
cancers (less than 10 mm in diameter) with a cure rate of zumab (Herceptin; Genentech) directed against HER-2/c-Erbmore
than 75% (300–302). There is some early evidence that B2, and (2) inhibitors of the tyrosine kinase region of the recep-
EBUS can be used to select for tumors in the large airways that tors such as ZD 1839 (Iressa; AstraZeneca, Wilmington, DE)
are sufficiently localized (i.e., have not extended beyond the and OSI-774 (Tarceva; OSI Pharmaceuticals, Melville, NY). So
airway cartilage) to be treated by PDT with curative intent, as far, only ZD 1839 and OSI-774 have progressed to Phase III
an alternative to surgery (303). In addition, McCaughan and studies in NSCLC. There are currently two multicenter Phase
coworkers treated 16 patients with Stage I NSCLC who were III trials of chemotherapy (carboplatin plus paclitaxel in one
not candidates for surgery. The patients had a 93% 5-year sur- study, and cisplatin plus gemcitabine in the other) alone or in
vival (304). PDT has also been assessed for use as a palliative combination with ZD 1839 in newly diagnosed patients with
treatment and has been shown to perform as well as other modal- advanced Stage III/IV NSCLC. Both trials completed enrolment
ities, in particular the Nd:YAG laser, in relieving endobronchial of chemotherapy-naive patients in late 2001. Two similar Phase
obstruction by NSCLC (304, 305). However, care must be taken III studies are in early stages, and plan to compare chemotherapy
as the time lag between treatment and tissue necrosis means (carboplatin plus paclitaxel in one study, and cisplatin plus gemthat
PDT is not suitable for emergency relief of obstruction, citabine in the other) alone or with OSI-774, again in chemother-
and in addition, obstruction may worsen because of the intense apy-naive patients with advanced stage NSCLC. The primary
inflammatory response at 24–72 hours posttreatment, so that end point for all four trials is survival.
bronchoscopy and resuscitation equipment must be available. To date, several potent synthetic inhibitors of MMPs
THE FUTURE
(MMPIs) have been produced and tested in patients. Many of
these made it to Phase III trials in advanced lung cancer but,
disappointingly, most of these trials were halted following a
The disappointing prognosis for patients with lung cancer has poorer outcome in the treated group. It is not clear why the
prompted nihilism on the one hand and determination to im- results were so poor, but it has been suggested that MMP inhibiprove
outcomes on the other. This has led to a search for new tion is needed at the time of angiogenesis and not once the
agents to complement the antitumor effects of chemotherapeutic tumor microvasculature has been established. So that although
drugs. Several observations of lung tumor biology have influ- a Phase III trial of one such agent, prinomastat (AG3340; Pfizer,
enced the selection of candidate drugs, many of which have New York, NY) in advanced (Stage IV) NSCLC was halted
been designed to affect specific cellular pathways implicated in in August 2001, patients with earlier (Stage IIIB) disease are
oncogenesis. Angiogenesis is thought to play an important role currently being recruited into a Phase II trial comparing standard
in tumor growth and metastasis. Successful blood vessel forma- chemotherapy with and without the MMPI. A Phase III trial of
tion lies in a balance between proangiogenic factors, such as another MMPI, BMS-275291 (Bristol-Meyers Squibb, Princeton,
the growth factors vascular endothelial growth factor (VEGF), NJ), in combination with paclitaxel and carboplatin, is currently
platelet-derived growth factor (PDGF), transforming growth open for patients with advanced NSCLC. Neovastat (AE-941;
factor (TGF), and epidermal growth factor (EGF) acting through Aeterna, Quebec, PQ, Canada), a naturally occurring MMPI
their receptor tyrosine kinases; the degradation and remodeling extracted from shark cartilage extract, significantly improved
of the extra cellular matrix by matrix metalloproteinases (MMPs) survival in patients with inoperable Stage III and IV NSCLC
and their inhibitors, the tissue inhibitors of matrix metalloprotei- and recruitment has begun for a Phase III trial in inoperable
nases (TIMPs); and the naturally circulating antiangiogenic mol- Stage III NSCLC in combination with platinum-based chemo-
ecules angiostatin (306) and endostatin (307). Some observations therapy (cisplatin and vinorelbine or carboplatin and paclitaxel)
in lung cancer itself have reinforced the idea that inhibiting and radiotherapy. Another inhibitor of angiogenesis is carboxya-
angiogenesis might prove fruitful. For example, in a study of mido-triazole (CAI); how it works is not entirely clear, although
143 patients with fully resected primary NSCLCs, the median it is known to inhibit calcium-mediated signal transduction. A
survival of patients with angiostatin-negative/VEGF-positive tu- randomized Phase III study of oral CAI in patients with admors
was significantly less than those with angiostatin-positive/ vanced NSCLC, who have received chemotherapy, is recruiting
VEGF-negative tumors, 52 versus 184 weeks, respectively. Intra-
patients and aims to assess the safety of CAI and to collect data