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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