Intratumoral chemotherapy is a novel interventional bronchoscopy technique, which involves injection of 1 or several conventional cytotoxic drugs directly into the tumoral tissue through a flexible bronchoscope by means of an ordinary transbronchial aspiration biopsy needle. Intratumoral chemotherapy deals with the selective destruction of malignant cells through the cytotoxic effects of anticancer drugs but spares normal tissue. In fact, the selective action of anticancer drugs on malignant cells has a similarity to brachytherapy and photodynamic therapy.
In addition to the advantage of initial eradication of tumoral burden inside the obstructed airways, maintenance of weekly intratumoral therapy for 6 to 8 weeks also provides a therapeutic effect of locoregional chemotherapy. Indeed, in newly diagnosed patients, the intratumoral chemotherapy constitutes a neoadjuvant therapy for irradiation or the other conventional cancer treatments.1
HISTORICAL BACK GROUND OF INTRATUMORAL INJECTION OF CHEMOTHERAPEUTIC AGENTS
The earliest clinical reports for direct intratumoral injection of chemotherapy were more than 40 years ago. This study involved patients with far-advanced cancers of the breast and liver.2 Brincker, in his general review of intratumoral chemotherapy, did draw attention to generally significant tumor regression after intratumoral chemotherapy. At this study, patients were initially treated weekly and then at intervals 4 to 5 weeks as regression was observed.3
Hayata et al was the first to develop the flexible needle for intratumoral injection through a bronchoscope in the early 1970s. In that study, the direct injection of Bacille Calmette Guérin (BCG) and some anticancer drugs into endobronchial tumors or infiltrated mucosa was used to manage endobronchial exophytic tumors and to relieve obstruction.4
Direct injection of anticancer drugs into the malignant endobronchial tumors has been successfully tested and used by Celikoglu et al. at the Cerrahpasa Medical Faculty of Istanbul University since 1986.5–7 In the beginning, the intratumoral chemotherapy was applied mostly for palliation of the bronchial obstruction in patients having relapse after previous conventional cancer treatments. The studies of Goldberg demonstrated that the injected cytotoxic drugs into the tumor also provide a locoregional chemo- or immune therapy in addition to the debulking effect.1 In view of these studies, since 1998, we are using the intratumoral chemotherapy with cisplatin in patients with newly diagnosed inoperable lung cancer as an adjuvant locoregional chemotherapy before administration of radiotherapy.8
TECHNIQUE AND EQUIPMENT FOR THE INJECTION OF CYTOTOXIC DRUGS THROUGH A FLEXIBLE BRONCHOSCOPE
Intratumoral chemotherapy can be performed through any model of standard flexible bronchoscope under local anesthesia on an outpatient basis. This mode of treatment does not require any special accessory except an ordinary transbronchial aspiration biopsy needle, which is available in the majority of endoscopy departments.
Patients undergo routine bronchoscopy with standard monitoring in a fully equipped bronchoscopy suite. Before the bronchoscopy, routine clinical data are obtained, including arterial blood gases, coagulation parameters, and routine biochemistry. The chest radiography and computerized axial tomographic (CAT) scan of the chest should be carefully reviewed to locate with precision the extent of the extraluminal localization of the tumor. An intravenous access site is established, and normal saline is infused during the procedure. Monitoring includes an electrocardiogram, noninvasive blood pressure recording, and oxygen saturation. Supplemental oxygen, 5 to 7 L/min, is administered nasally. Topical anesthesia of the oral–nasopharynx is achieved with 4% lidocaine. Conscious sedation is achieved with 3 to 5 mg intravenous midazolam and meperidine.
With the patient in the sitting position, the flexible bronchoscope is passed through the nose or orally in the conventional fashion, and a full inspection of the tracheobronchial tree is completed. The operator inspects the lesions to be treated, whether they are projecting into the airway or infiltrating the mucous membrane, and to define their position and the extent of stenosis or extrinsic compression that could exist. Direct endoscopic intratumoral therapy is then performed using a flexible needle, which is passed through the working channel of the bronchoscope. Size and length of the needle is selected according to the type of obstruction and tumor growth. In addition to the bronchoscopist, the procedure requires a dedicated assistant.
The device that is designed for transbronchial needle aspiration biopsy through a flexible bronchoscope can be used with the administration of chemotherapeutic agents into the tumoral tissue.5–8 Injection was made at the site of endobronchial or extraluminal lesions.
The selection of the size and length of the needle depends on the type and localization of the tumor. For exophytic, polypoid intraluminal lesions, 19- to 23-gauge, 10- to 13-mm long needles; for submucosal lesions, 23-gauge, 5- to 6-mm long needles; and for the peribronchial masses and extramural mediastinal or hilar lesions, a 21-gauge, 15-mm long needle with a stiffer catheter should be used. To prevent damage to the working channel of the flexible bronchoscope, all needles should be of a retractable design.
HOW TO INJECT THE ANTICANCER DRUG INTO A TUMOR
The needle device is advanced through the bronchoscope’s working channel in the retracted position. The tip of the needle device is visualized and once the tip of the device is approximately 20 mm above the area to be injected, the needle can be advanced from its sheath. At this point, it is usually helpful to withdraw the needle’s sheath in the bronchoscope channel so that only the needle remains exposed. This maneuver allows the sheath to be supported by the bronchoscope channel and gives the operator greater control over the exact placement and advancement of the needle.
The mode of insertion of the needle could vary, depending on the appearance of the lesion to be treated. If the tumor is bronchoscopically visible as an intraluminal polypoid or exophytic mass, the needle is inserted directly into the tumor itself or surrounding bronchial membrane (Fig. 1). When an infiltrating malignant lesion on the bronchial wall is present, the needle is inserted at an oblique angle into the infiltrated membrane or submucosal cancerous infiltration (Fig. 1C). In the case of compression of the airway lumen by an extraluminal tumoral disease, either mass or metastatic lymph nodes, which its location and extension was defined previously by a CAT scan, the needle is inserted perpendicular to the wall of the airway (Fig. 1D). Once the needle is embedded in the tumoral tissue, the drug is injected. Although injection is applied, the needle is moved back and forth in a fanning manner to obtain maximum dispersion of the drug throughout the tumoral tissue. Certainly, it is important to withdraw the needle into its sheath before removing it from the bronchoscope.
In reality, many endoscopists, when they perform routine transbronchial needle aspiration, use a specific intratumoral chemotherapy technique in an opposite manner. In both procedures, the needle is initially embedded into the tumoral mass or infiltrated mucosa. However, after embedding the needle, in intratumoral chemotherapy, a certain quantity of a drug solution is injected into the tumoral tissue; in contrast, in the course of the transbronchial needle biopsy, some material is aspirated from the tumoral tissue.
What Happens During and After Injecting the Cytotoxic Drug Into the Tumor?
When the tumor is visible through the bronchoscope as an intraluminal exophytic mass, injection of the cytotoxic drug produces the following endoscopically visible effects.
While injecting the cytotoxic drug, the surface of the tumor around the needle becomes paler and whiter. This is probably the result of swelling of the tumoral tissue by added volume of a liquid in a restricted space.
Shortly after local administration of the drug, there is a reduction in size of the tumor and accompanying changes, ie, atelectasis or obstructive pneumonia. When tumor infiltrates into the bronchial membrane, the infiltrative tumoral changes improve markedly by the direct injection.
Intratumoral injection of cytotoxic drugs also provides a hemostatic effect on tumor tissue. In general, bleeding on the surface of the tumor stops after injection. The hemostatic effect probably is the result of a vasoconstriction of the small vessels in or around the tumor mass. This could occur because of a reaction of vessels to the very high concentration of cytotoxic drug. Also, the volume of drug solution added by injection in a restricted space could compress the vessels inside the tumor. This could cause an oligemia in the tumor bulk contributing to hemostasis. Intravascular formation of thromboses, which probably occurs after the cytotoxic drug injection, could contribute to the hemostasis as well.
The beneficial debulking effects of intratumoral administration of cytotoxic drug on tumoral tissue presumably occur as a result of the contact of tumor cells with a very high concentration of anticancer material, which causes an instant necrosis, and consequently the reduction of the tumor volume.
The Quantification of the Volume of the Drug Solution
When the injection could not be carried out any more in an insertion point as a result of resistance of the tissue, then the needle is taken back and inserted again into another point. This maneuver continues at several points on the surface of the tumor until the desired dose of the drug has been administered into the entire malignant tissue. Generally, a large volume (several cubic centimeters) of a solution can be injected into an exophytic tumor. Actually, exophytic tumors in the bronchial lumen have a spongy consistency and a very high volume of a solution could be injected without much resistance.
Even when only a small part of the tumor is visible through the bronchoscope, the intratumoral chemotherapy is also useful in decreasing the size of the entire tumor. This fact suggests that anticancer drugs injected through a bronchoscope might infiltrate and diffuse deeply into all parts of the tumor bulk.
In subsequent follow-up endoscopic inspections, a whitish/yellowish gel-like substance consisting of fibrin plugs and necrotic cell debris of the tumor tissue, attached to the surface of the drug-injected areas of the tumor or infiltrated mucous membrane, is observed.
MECHANICAL PROCEDURES FOR DEBULKING OF THE TUMOR AS A SUPPLEMENTARY METHOD TO INTRATUMORAL CHEMOTHERAPY
The injected cytotoxic drug into the tumoral tissue kills or devitalizes the cancerous cells but does not eradicate or remove them. Although, in the majority of cases after the first session of the intratumoral chemotherapy, the reduction in volume of the tumor is sufficient to alleviate symptoms, in some cases, the shrinkage of the tumor is not sufficient to restore air passage as quickly as required. This occurs especially in tumors with involvement of the trachea or main bronchus and carina. In these cases, the debris of devitalized cells, necrotic residues, and fibrin sloughs should be removed by other interventional procedures such as laser photoresection, or electrocautery or cryotherapy. When such equipment is not available, we recommend removing necrotic tumoral residue by mechanical procedures such as piecemeal resection with foreign body forceps and scraping with the tip of a bronchoscope (Fig. 1B). In fact, these mechanical techniques were the oldest and easiest ones among the endoscopic procedures. Large pieces of tumor can be removed with forceps.9 The procedure could give instant relief, provided that functional parenchyma can be recruited and a pulmonary artery is open. However, bleeding is inevitable with such mechanical interventions. Therefore, whenever mechanical removal of tumor residue is attempted, a coagulation method should be combined with such mechanical removal. For that reason, this simple interventional procedure did not gain much favor. However, the added benefit of intratumoral injection of cytotoxic drugs provides a hemostatic effect on tumor tissue. The prevention o f bleeding by intratumoral chemotherapy allows removal of the tumor residue by piecemeal resection without bleeding.
After intratumoral chemotherapy, exophytic or polypoid tumoral structures in the airway lumen become brittle and easily separable into smaller fragments. This effect facilitates detachment of the tumor residues from the airway wall by moving the tip of the bronchoscope back and forth. Scrapping by bending the tip of the bronchoscope also could help the detaching some surface-attached residual necrotic tumor debris. The smaller fragments could be removed by irrigation and suction or sometimes coughed up.
In cases with complete obstruction of a major airway by an exophytic or polypoid tumor, which occupies only a short length in the airway lumen, sometimes with a pushing movement, the tip of the bronchoscope can pass through the occluded area and the airway lumen immediately opens. Thus, the pus collected in the postobstructive region of the airway can be eliminated by suction and irrigation.
In patients with mixed tumors, the removal of the necrotic intraluminal component of the tumor bulk exposes the base of the extramural component of the malignant tissue on the bronchial wall. After removal of the tumoral debris, the length of the needle becomes sufficient to reach the extramural component of the tumor. This way, an additional amount of cytotoxic drug can be injected into the extramural component of the tumor at the same treatment session.
The cases in which recanalization is not satisfactorily obtained by piecemeal resection, dilatation with angioplasty balloon catheters can also be used as a mechanical procedure.
In some cases, the success of recanalization by intratumoral chemotherapy and mechanical procedures could be transient. In such cases, stent insertion should be a longer-lasting effect.
Intratumoral chemotherapy does not require any particular immediate follow-up care. Patients treated under local anesthesia and conscious sedation have been sent home on the same day of intervention.
Reexpansion the collapsed area of the lung can be confirmed with a chest x-ray. Nevertheless, we recognize the delayed effect of necrosis from injection of cytotoxic drug and generally do not expect a change in the chest film immediately. Corticosteroids are not routinely administered and are considered only after treatment of laryngeal and tracheal lesions, in which the risk of an edematous reaction is greatest. The hemostatic effect of cytotoxic drug injection is often sufficient to stop hemoptysis. Improvement could be delayed and occurs only some hours to a day after intratumoral injection.
In some patients with obstruction of the trachea or carina plus of the main bronchi, dyspnea could be worsened 1 to 6 hours after the first session of intratumoral injections. This could be the result of reactive edema, accumulation of necrotic tumor cell coagulum, and inspissated secretions. In such patients, 4 mg dexamethasone is administered intravenously to decrease the reactive edema at the intratumoral injection site. A cleanup bronchoscopy is performed immediately with removal of necrotic tumor debris and accumulated secretions by piecemeal resection with forceps and suction. This cleaning procedure immediately restores the opening of the airway lumen with the alleviation of dyspnea.
In patients with postobstructive pneumonia at the initial session after debulking, the pus built up beyond the postobstructed airways must be carefully removed by suction. Otherwise, the pus spills out of the healthy airways. The intratumoral necrotic tumor debridement also allows injection of cytotoxic drug more deeply into any residual tumor mass attached to the bronchial wall in mixed tumors.
SELECTION OF THE CYTOTOXIC DRUGS FOR INTRATUMORAL CHEMOTHERAPY
Drugs that do not induce local necrotic changes in the normal mucosa, which have a pH of approximately 7.4, and that exhibit direct antineoplastic activity should be selected for this type of locoregional chemotherapy. Drugs that require activation by hepatic microsomes before antineoplastic activity is present (eg, cyclophosphamide) were considered unsuitable for direct injection.
At present, in our clinical practice, we have been using anticancer drugs prepared for intravenous administration, which are available on the market. As a result of the short half-lives of most cancer drugs, polymer-drug compositions that can enhance drug stability and prolong local activity with limited diffusion away from the tumor site are important to the intratumoral modality. Drug-loaded microspheres, liposomes, and polymer gels could offer potential benefits for much more successful intratumoral therapy in the future.1
In our previous studies, we have used a mixed drug regimen consisting of methotrexate, bleomycin, mitoxantrone, mitomycin, and 5-fluorouracil5,6 for intratumoral injection. In subsequent studies, we have used 5-fluorouracil alone for intratumoral treatment, and we have obtained similar satisfactory results of debulking as we obtained with a multidrug regimen.7
In recent clinical trials, the most active single agent against nonsmall cell lung cancer (NSCLC) frequently used in a systemic combination chemotherapy approach is cisplatin.10,11 Additionally, intratumoral administration of cisplatin has been successfully used for locoregional chemotherapy in the treatment of a variety of localized malignant tumors. It is administered by direct injection in head and neck cancers,12 by CAT-guided injection in malignant liver tumors,13 by injection through endoscopes in gastric tumors,14 and in the palliation of obstructive cancer of the esophagus.15 In view of the successful results of these studies, we started to use cisplatin in our clinical practice for intratumoral chemotherapy through a bronchoscope, especially in newly diagnosed inoperable NSCLC cases before external radiotherapy.8
Dosage of the Cisplatin
Cisplatin solution at a concentration of 4 mg/mL has been used for intratumoral chemotherapy. Theoretically, approximately 2 mg cisplatin per cubic centimeter of tumor should be injected into the tumor. Calculation of tumor volume is important for the treatment of the extramural component of the tumor. Tumor volume is calculated on a computerized tomographic image by using the formula 0.5 × L × W × H, where L is the greatest length, W is the greatest width, and H is the greatest depth or height of the tumor.15 In some exophytic tumors, more volume of solution can be injected without any resistance.
In practice, instillation of the drug continues until the tumoral tissue contains the highest possible volume of the solution. In other words, injecting the drug should be continued until no more volume of the solution can be administered. Then the needle is withdrawn and inserted at another point on the tumor surface keeping the total amount to less than 40 mg/cycle.
Approximately 70% to 80% of patients respond within 6 to 8 courses of intratumoral chemotherapy; the tumoral area on the airway wall heals with the restoration of a normal ciliated epithelium without stenosis.5–8
Schedule of the Intratumoral Chemotherapy Sessions (Cycles)
In newly diagnosed inoperable cases, direct injections are carried out weekly for 3 weeks (days 1, 8, 15, and 21). Thereafter, radiotherapy is started.
If a tumor occludes the airway in a patient relapsing after conventional cancer treatments, maintenance intratumoral chemotherapy continues weekly for 6 to 8 weeks or more (days 1, 8, 15, 22, and so on). If the obstruction is relieved and the bronchial lumen remains open, bronchoscopy controls should be repeated monthly for 4 to 6 months and then 3 monthly for 1 year if the patient is alive.
If symptoms of obstruction are still persisting without any alleviation after the initial intratumoral treatment, a cleanup bronchoscopy can be performed in 2 or 3 days. If an important volume of intraluminal tumoral bulk is still endoscopically observed, then a further dose of cytotoxic drug is injected.
THE EFFICIENCY AND PLACE OF INTRATUMORAL CHEMOTHERAPY AMONG THE OTHER INTERVENTIONAL BRONCHOSCOPIC PROCEDURES
For application of the intratumoral chemotherapy, the lesion must be visible endoscopically and be accessible to the needle through the bronchoscope. Lesions that are polypoid, of short length, have a large endobronchial component, and have a functioning lung distal to the lesion have mostly benefited from intratumoral chemotherapy.
Lesions that have a large extraluminal component, that do not allow any visibility beyond the lesion, and that occupy more than 4 cm of length in the airway are counter indicated for laser photoresection, electrocautery, or cryotherapy. Long, tapering lesions or those with extensive submucosal involvement also are not favorable for these thermic interventions. Fortunately, intratumoral chemotherapy could be effective in such cases. In addition to the benefit of debulking of the airway lumen, intratumoral chemotherapy has an additional synergistic effect for other therapeutic modalities such as extra beam irradiation.
In recent clinical studies, systemic administration of cytotoxic drugs before radiotherapy have been used extensively as neoadjuvant chemotherapy with improvement of survival.16 As a consequence, safer and more aggressive (higher-dose) administration of toxic chemotherapy or immunotherapy directly to a tumor site, ie, intratumoral therapy, could be considered an attractive alternative to systemic treatment. Indeed, our recent study indicates potentiating or synergistic effect with the combined treatment of intratumoral chemotherapy and irradiation.8
Intratumoral chemotherapy through a flexible bronchoscope can be added concomitantly or any time after conventional lung cancer treatment modalities. It is a novel locoregional chemotherapy procedure and as such should be integrated into the plan of action of treatments for bronchial carcinomas. In reality, the interventional procedures must not compete with each other but should supplement each other. Therefore, the introduction of alternative techniques based on the different principles such as intratumoral chemotherapy will be useful in the management of malignant airway obstruction and endobronchial tumors.
Intratumoral chemotherapy is a novel therapeutic concept in the management of malignant airway obstruction.
Intratumoral chemotherapy offers an alternative therapy for endobronchial tumor ablation with significant safety as well as being extremely inexpensive.
This very efficient therapeutic measure without any serious morbidity, which is available and easily applicable in all routine bronchoscopy laboratories, not requiring any special experience of the physician, not interfering with future definitive therapy, and economical, should be used more extensively in the treatment of endobronchial malignant obstructions.
Intratumoral chemotherapy has been regarded as an integral part of an oncologic concept. It does not compete with any other interventional bronchoscopic procedures, surgery, irradiation, or systemic chemotherapy, but supplements these therapies.