Lung cancer therapy
Abbreviations: 5-fluorouracil, (5-FU); computerized axial tomography,
(CAT); endobronchial intratumoral chemotherapy, (EITC); endoscopic
ultrasound bronchoscope, (EBUS); intratumoral (IT); Sentinel lymph
nodes, (SLN)
ABSTRACT
Stage III A& B bronchial carcinoma presents in a heterogeneous group of
patients. Because of uncertain prognosis, the proper therapeutic strategy
for these patients is a controversial subject for oncologists.
This group of patients encompasses those with locally advanced disease
and frequently presents with airways obstruction that can be life
threatening. Clinical studies have demonstrated that immediate relief of
obstruction by interventional bronchoscopic procedures, before
treatment by radiotherapy or intravenous chemotherapy, can improve
patient quality of life and survival The removal of an obstructive tumor
mass within the major airways has usually been achieved by ablation
techniques such as laser photoresection, electrocautery or cryotherapy.
Other interventional bronchoscopic modalities such as brachytherapy or
photodynamic therapy have usually not been considered as a first choice
for treatment because of the slower response in opening airways in
patients with life-threatening obstructions.
During the past 10-15 years, the direct bronchoscopic injection of
cytotoxic drugs into the tumor mass, i.e. "endobraonchial intratumoral
chemotherapy (EITC)”, has proven to be an effective new endobronchial
treatment paradigm. EITC is a form of neo-adjuvant chemotherapy which
can relieve endobronchial tumor obstruction without adverse toxic side-
effects. This improved neoadjuvant treatment strategy for Stage IIIA&B
bronchial carcinoma accompanying NSCL cancer is reviewed here.
Keywords: Lung cancer, Bronchial obstruction, Bronchoscopy,
Endobronchial intratumoral chemotherapy
Running title: Bronchoscopic intratumoral chemotherapy for stage III A&B
lung cancer with airway obstruction
1- INTRODUCTION
More than 1 million cases of lung cancer are diagnosed worldwide each
year [1], approximately 80% of which are non-small cell type [2],
comprising squamous cell carcinomas, adenocarcinomas, and large cell
carcinomas).
Many patients are first diagnosed with advanced disease and 5-year
survival for all stages of disease is only about 14% [3]. Surgery is
generally regarded as the best treatment option, but in only about 25 % of
non-small cell lung cancer (NSCLC) are tumors suitable for potentially
curative resection [4]. A further 20% of patients with locally advanced
disease undergo radical thoracic radiotherapy. The remaining patients,
with late-stage or metastatic disease, are usually given only palliative
treatment [5]
1.1 Tumor subgroups according to characteristics that influence prognosis
In Stage III lung cancer, the most important factors influencing prognosis
are: 1-extent of mediastinal lymph node involvement; and 2- extent of
endobronchial involvement:
1. Sub-grouping of tumors according to the extent of mediastinal
lymph node involvement
Patients with positive mediastinal lymph nodes form the largest subgroup
within stage IIIA NSCLC. Even within such subgroups, the outcomes are
not uniform among patients because it has been shown that the volume or
extent of nodal disease also has prognostic import [6- 8]. Patients with
low-volume or microscopic mediastinal nodal involvement have a five year
survival of 25-40% when treated with surgical resection alone, whereas
the same treatment in patients with macroscopic N2 metastases results in
less than 10% 5-year survival. [6- 8]. Similarly, survival in a T4 tumor with
N0, N1, N2 nodal invol vement should be different than in T4 tumor with N3
nodal involvement although both sub groups are staged within the IIIB
category.
2. Sub-grouping of tumors according to location inside the airways
The location of tumor inside the airway lumen is also a very important
factor in the assessment of TNM staging, prognosis and the results of
treatment. Unfortunately the unfavorable effects of endobronchial tumor
location is rarely taken into consideration in deciding upon therapeutic
strategies and assessment of results. In fact, it has been demonstrated in
several studies that the complications generated by airway obstruction
often confuses proper prognostic assessment and may therefore adversely
affect the quality life of the patient. In particular, infectious
complications and the deterioration of pulmonary function caused by
occlusion of airways can constitute a problem for the successful use of
conventional treatments [9 -11].
The efficacy of traditional treatment modalities such as radiotherapy or
systemic intravenous chemotherapy on endobronchial tumors causing
obstruction is limited [12- 13] . However, several studies have
demonstrated that the removal of endobronchial tumor obstruction by
interventional bronchoscopic procedures may be quickly effective and
without significant risk (mortality ≪ 0.5 %). This is accompanied by
improvement in the quality of life and prolonged survival when combined
with the traditional treatment modalities such as radiotherapy or systemic
intravenous chemotherapy [14 , 15, 16].
The aim of this paper is to consider the major multi-modality studies that
have helped define the current standard of care for the particular disease
subsets of stage III NSCLC with airways occlusion, and to also provide a
strategic basis for ongoing and future research initiatives.
2. SUB-GROUPING OF STAGE IIIA AND IIIB NSCLC
ACCORDING TO THE LOCATION AND BULK OF TUMOR
IN THE AIRWAY LUMEN
2.1 The international TNM staging system
For patients w th NSC lung cancer, the anatomical extent of disease
will guide the treatment and prognosis and may thereby influence
survival. Non-small cell lung cancer is routinely staged using the
International Staging System; the TNM system ("T" for extent of primary
tumor, "N" for regional lymph node involvement, and "M" for metastases)
According to this TNM staging system the extent and situation of primary
tumors in the airway lumen are not categorized as a distinct subset [17,
18]. However, studies have demonstrated that the accurate evaluation of
treatment strategies for improved survival is significantly influenced by
the location of the tumor in the airway lumen and the degree of
obstruction [14, 15, 19].
Our clinical experience shows that in stage III A&B patients the extent of
endobronchial involvement of the primary tumor, regardless of other
disease characteristics, significantly influences survival and is one of the
most important factors to be considered when prescribing treatment
modalities and evaluating results [20, 21]. We therefore believe it can
be very helpful to describe a distinct sub-group of patients in the
international classification staging system which includes a
description of the location of bronchial involvement of the primary
tumor. In this sub-grouping, the TNM descriptors are kept as the
same as defined in the International System [17] but an extra
descriptor should be added to define the location and extent of a
primary tumor in the airway lumen.
2.2 The advantage of sub-grouping tumors according to airway
involvement
For a NSCLC patient whose tumor is staged according to the International
Staging System as T3 or T4 (because the tumor location is in the airway
regardless of other disease characteristics), staging becomes III A or
III B. But this patient could have nodal involvement as N0, N1 or N2 or an
isolated 1cm tumor in the lung parenchyma. Therefore, the prognosis and
therapeutic strategy for treating the tumor located in th e airway may not
be adequately analyzed. In short, for proper planning of a treatment
Strategy in patients staged as “III A&B”, regardless of other disease
characteristics, the specific effect of the tumor location inside the airway
should be considered. Therefore, in addition to current NSSLC staging an
additional factor (such as 'T airway' ) would be helpful to demonstrate the
status of the tumor “T” in the airways.
3. BRONCHOSCOPIC INTRATUMORAL CHEMOTHERAPY
3.1 Endobronchial Intratumoral Chemotherapy (EITC)
Endobronchial intratumoral chemotherapy (EITC) is a relatively new
procedure for treatment of lung cancer. This procedure involves the direct
injection of conventional cancer drugs into tumor tissue through a flexible
bronchoscope by means of a needle catheter. The concept and technique
have been described in detail in previously published papers [35-37]. Our
emphasis in this paper is on the potential benefit for the use of EITC as a
neoadjuvant procedure before surgery or external radiotherapy for stage
III A&B NSCLC presenting patients with endobronchial tumors.
3.2 EITC Procedure
For intratumoral chemotherapy, various approved cancer drugs have been
used including 5-FU, mitoxantrone, methotrexate, and cisplatin. Cisplatin
has been used in our recent EITC studies to treat NSCL cancer patients and
is administered in solution as available in hospital pharmacies for intra-
venous drug delivery [35-37]. Cisplatin may be injected into a tumor mass
at a concentration of 0.5 - 4 mg/mL at a volume of 0.5-1 mL of drug
solution injected for each cc of tumor volume . The total dose is delivered
by multiple injections at several different sites on the tumor mass. Usually,
0.5-2 mg cisplatin is administered at each injection point. Although the
total dose of cisplatin delivered by intratumoral injection is based on the
estimated total volume of the tumor mass, the maximum total dose is
usually not more than 60 mg of cisplatin delivered at each IT injection
session. The EITC therapy regimen consi
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