A New Treatment Strategy for Stage III Lung

 

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 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 involvement 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 seldom 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 of 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 with 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 the 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 patients presenting 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 consists of weekly injections, usually of 

4x sessions during a 3-week period (days 1, 8, 15, and 22) [35-37].

3.3. video konacak 

3.3 EITC prior to surgery as a neoadjuvant loco-regional 

chemotherapy

Preclinical animal IT chemotherapy studies and early human have 

provided safety and efficacy data for more extensive human studies [37, 

38]. 

These studies have indicated: 

(1) ability to provide localized super dosage of cytotoxic drugs 

(2) rapid necrosis and tumor shrinkage to facilitate subsequent 

without systemic toxicity

tissue-conserving surgery when used as a neoadjuvant treatment

(3) ability to more effectively treat patients initially presenting with 

(4) no patient discomfort and complications normally associated with 

(5) the potential for a tumor necrosis induced systemic tumor-

inoperable cancers 

conventional chemotherapy 

specific immune response; reported in animal studies (needs  

verification in human studies)

(6) transport of drug molecules via afferent lymphatic vessels to the  

          sentinel and regional lymph nodes; thus, EITC has the potential to     

          eradicate occult micro-metastases in mediastinal lymph nodes. 

3.4 Importance of EITC for lymph node micro- metastases

At present, surgical resection offers NSCLC patients the best chance for 

survival. Surgery may be curative for stage I and stage II disease.  

Patients with stage IIIA disease, in certain conditions, may also be 

candidates for surgical resection. However, for patients with stage IIIB 

disease, the tumors usually are considered unresectable, unless they are 

down-staged by neo-adjuvant radio-chemotherapy or by one of the 

interventional endobronchial therapeutic modalities.  Patients with stage 

IV disease have distant metastases and are offered only non-surgical 

treatments, with the exception of rare cases of resectable solitary 

metastasis in a patient who also has a resectable primary lesion [39, 40].

In general, only 25 % of lung cancer patients are considered candidates at 

presentation for potentially curative resection [4]. This depressing 

situation is due to early local metastatic lymph node dissemination of the 

tumor which occurs during growth of most primary malignancies.  Indeed, 

it has been suggested that 20-25% of patients initially considered to have 

stage I disease are recognized during surgery to have mediastinal lymph 

node metastases [41, 42].

As a general rule, if a nodal involvement is recognized, the chances of long 

term survival are less than 50% [43, 44]. Therefore, in order to ameliorate 

this unfavorable outcome of the patients who are eligible for surgical 

resection, some particular safety measures must be taken into account for 

mediastinal lymph node metastases.  Animal and human clinical studies 

have demonstrated that sentinel lymph nodes (SLNs) are the first 

lymphatic drainage site of a tumor and the likely site of initial metastatic 

tumor cell dissemination (Tiffet et al, 2005) [45]. Although the overall 

prognostic significance SLN micro-metastases in early lung cancer remains 

unclear, recent studies suggest that for larger and potentially resectable 

lung cancers there is a significant 5-year survival advantage in patients 

with adenocarcinoma who do not have SLN micro-metastases when 

compared to patients with SLN micro-metastasis (62% with metastasis vs. 

86% with no metastasis) [46].

The animal studies have demonstrated that intratumoral (IT) injected drug 

molecules can be transported by afferent lymphatic vessels into the 

sentinel and draining lymph nodes. Such drug transport to the lymph 

nodes may be expected to have a beneficial therapeutic effect by 

eradicating the lymphatic micro-metastases. Clinical studies performed 

using pre-surgical administration of radioisotopes; blue dye techniques 

and even the blue cancer drug mitoxantrone [48], support this view of 

drug molecule transport from an IT injected site to sentinel and draining 

lymph nodes [45-49]. This is also indicated by the studies of Lardinois et al 

in which a marker drug injected through the bronchoscope into normal 

tissues around the tumor is observed to be transported to sentinel lymph 

nodes. We deduce from this that cytotoxic drug injection into tumor  may 

have the added advantage for stage IIIA&B NSCLC of inhibiting metastasis 

by cytotoxic action on tumor cells which are migrating into the lymph 

nodes that drain the tumor area [49].

3.5 Clinical trials with preoperative (neoadjuvant) intravenous 

chemotherapy to support the potential benefit of intratumoral 

injection of cytotoxic drugs

The suggested beneficial effects of intratumoral injection of  cytotoxic  

drugs on micro-metastases in loco-regional mediastinal lymph nodes tends 

to be corroborated by the results of neoadjuvant intravenous (systemic) 

chemotherapy clinical trials.

During the past decade, the findings of phase III clinical trials have 

emphasized that patients with resectable disease have improved survival 

with preoperative induction (neo-adjuvant) systemic intravenous  

chemotherapy.  Moreover, several trials have shown that a pathologically 

complete response in mediastinal lymph nodes predicts superior long-term 

survival after induction chemotherapy [50- 52]. The proposed benefits of 

preoperative intravenous chemotherapy are a reduction in tumor size such 

that tumors become easier to remove surgically, and the change of status 

for inoperable tumors to operable. Preoperative intravenous chemotherapy 

may also assist the early eradication of metastases that are clinically 

undetectable, which could lead to better control of distant recurrence. It 

has also been suggested by these studies that systemic chemotherapy 

given before surgery may be better tolerated than post operative 

chemotherapy since the patient is better able to cope with side effects 

when not recovering from major surgery.

According to the foregoing, a significant survival benefit is likely for 

patients with NSCLC who receive preoperative chemotherapy compared 

with those who do not [53].

There are, however, potential disadvantages to this systemic treatment 

[54-56] i.e.

 The systemic toxic effect of cytotoxic drugs could be so severe 

that patients die or therapy must be postponed.

 While the patients receive chemotherapy, a potentially curative 

operation is being delayed. If the chemotherapy is ineffective, 

this delay could prove detrimental and could lead to the disease 

spreading.                      

Since the preoperative delivering of cytotoxic drugs by endobronchial 

intratumoral injection (intratumoral  chemotherapy) avoids systemic toxic 

drug effects, preoperative intratumoral chemotherapy may prove to also 

be useful as a complement to systemic neoadjuvant chemotherapy with 

lower doses. 

5. CONCLUSIONS

It is now generally accepted that the best therapeutic option for newly 

diagnosed stage I and stage II NSCLC patients is surgical resection 

without delay. Stage IV treatment by intravenous (I.V.) chemotherapy and 

chemo-radiotherapy is regarded as palliative. However, for lung cancer 

patients with stage III disease, even though locally advanced, the 

appropriate therapeutic strategy is controversial and often unclear. Some 

thoracic surgeons favor immediate resection for operable stage IIIA 

patients without any induction therapy. If previously undetected 

mediastinal lymph node metastases is found during surgery, post-surgical 

radiotherapy or intravenous chemotherapy may be recommended.  

However, some oncologists will recommend in such patients neo-adjuvant 

intravenous chemotherapy prior to surgery reasoning that the induction 

chemotherapy may eradicate occult micro-metastases resulting in better 

outcomes [50-53].

In view of the beneficial results reported in clinical trials of pre-surgical 

intravenous (systemic) chemotherapy as well as our intratumoral chemo-

therapy  studies during the past 10-15 years [21], we now believe that 

endobronchial intratumoral chemotherapy deserves serious consideration 

for treatment prior to surgery, especially for stage IIIA&B NSCLC. 

Furthermore, EITC may be beneficially used in combination with  

conventional systemic chemotherapy and/or with radiotherapy [20, 57]. 

Because EITC is a cost effective, patient friendly, minimally invasive 

procedure that is not systemically toxic it should become a more routine 

part of the oncologist’s armament. The potential therapeutic value for   

attacking regional lymph node metastasis is also an important favorable 

factor. Although several non-randomized clinical studies indicate the value 

of EITC as a new NSCLC therapeutic paradigm, large randomized clinical 

studies remain to be conducted to fully validate the advantages of EITC, 

particularly for stage III NSCLC.  

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