The advent of photodynamic therapy (PDT) was one of the early advances in interventional pulmonology that elevated therapeutic bronchoscopy into the curative arena. First used by Hayata in 1982, PDT has not significantly changed in principle or application. PDT is based on the concept that malignant cells absorb and retain a photosensitive compound and become very sensitive to light. The photosensitizer is then activated with a light wavelength corresponding to the photosensitizer absorption spectrum that takes the singlet basic energy state to the goal excited triplet state. The excited triplet state leads to the generation of reactive oxygen species, which cause cellular damage and apoptosis of tumor cells.
The procedure involves three steps:
First step: intravenous injection of the photosensitizer agent porfimer sodium (Photofrin, Pinnacle Biologics, Bannockburn, IL, USA) at 2 mg/kg
Second step: 48 h after injection, performing a bronchoscopy and using a light diffuser through the working channel of scope to expose the sensitized tumor cell to a nonthermal laser light (wavelength of 630 nm)
Third step: 48 h after index procedure, performing a bronchoscopy to remove sloughed tissue with suctioning, forceps, or cryoprobe. If the intended lesion does not appear to be adequately treated, a second light treatment can be delivered at this session.
PDT can be used with curative intent for patients with carcinoma in situ or as adjunctive therapy or palliative treatment for malignant central airway obstruction.
Identifying the appropriate patient for PDT relies on selecting the optimal target lesion. If aiming for curative intent of carcinoma in situ, consider factors such as a lesion size <1.5 cm (<1 cm for optimal results), proximal airway location, and intraluminal disease. It is important to remember that the depth of tissue penetration for PDT is 4–6 mm. The therapeutic effects of PDT are delayed such that its application is limited in critical malignant central airway obstruction.
In the United States, Photofrin is the only approved photosensitizer compound available. It is dosed 2 mg/kg 48 h prior to bronchoscopy. After its administration, it is retained in tumor cells and cleared from most healthy issues in 6 h except for the lung, reticuloendothelial tissues, and the skin. The unique properties that allow for Photofrin to accumulate in malignant cells have not been well elucidated. Proposed mechanisms involve elevated numbers of lower-density protein receptors on tumor cells, decreased pH in the tumor microenvironment, and the presence of macrophages.
As mentioned earlier, Photofrin does not just accumulate in malignant cells but is highly concentrated in the spleen, liver, kidney, and orders of magnitude lower in the skin. Given that the spleen, liver, and kidney are protected from light, they are not considered when it comes to PDT. Photofrin can be retained in skin for up to 8 weeks after injection, requiring patients to be cautioned to avoid light. Emphasis should be placed on wearing protective clothing, gloves, and eye protection to avoid burns, which are usually mild in severity and are generally cited as occurring in 5%–28% of cases.
Bronchoscopy technician/respiratory therapist
PDT is typically performed in the bronchoscopy suite as an outpatient procedure. It can be done under moderate sedation or general anesthesia. Sedation should be deep enough for the patient as to not disrupt activation of light at the target lesion. Picking the procedural day for PDT is important, as a repeat bronchoscopy must be completed 2 days after the light activation procedure. Depending on staff and bronchoscopy suite scheduling, this usually precludes scheduling PDT on Thursday or Friday. The preprocedural preparation area should keep the lights dimmed to diminish ambient light thereby minimizing potential skin irritation. The same holds true for the bronchoscopy procedure room if possible.
Once the patient is sedated, the bronchoscope is introduced for an airway examination to ensure that the lesion has not significantly changed from when PDT was originally offered. A cylindrical diffuser, which comes in both rigid (outer diameter 1.7 mm) and flexible (1.07 mm) fibers, is attached to the diode laser machine. The diffuser fiber length is selected to match the length of the target lesion. Light is distributed in a 360-degree radius from the fiber when activated. Red light (625–630 nm) is the preferred light band, as it penetrates best into tissue, with 800 nm considered the limit to generating a photodynamic reaction. Tissue activation of 200 J/cm is the most commonly selected dose as it is the maximum that can be applied to the airway. The diffuser length is then selected on the calculation menu of the laser machine providing the time needed to deliver the desired light dose.
The diffuser, when introduced through the bronchoscope, is then placed in the middle of the airway across the target lesion. Special glasses are distributed to protect the eyes during energy activation. The bronchoscope is steadied and the catheter is maintained in the airway. While the diffuser is activated, bright light that renders the screen indiscernible occurs. Maintaining diffuser position is important to ensure direct delivery of the light to the target lesion. Once the activation is completed, the bronchoscope is removed and the patient is recovered and given discharge precautions regarding worsening respiratory distress and the importance of returning for repeat bronchoscopy. Reillumination can be offered to patients, as the Photofrin remains biochemically active in malignant cells for an additional 6 to 7 days from injection.
When the patient returns for repeat bronchoscopy 48 h after activation, the airway is inspected and denuded respiratory epithelium is removed. This is accomplished with suctioning and pulmonary forceps in most cases. A cryoprobe may be needed in some cases to remove very adherent or large amount of sloughed tissue. Once the sloughed tissue is removed, the patient is recovered and discharged home. Repeat bronchoscopy 1–3 months after PDT should be performed to assess the treated area is free of disease.
Figs. 9.1–9.5 show bronchoscopic images of a PDT procedure performed to treat a carcinoma in situ in the bronchus intermedius.
There are some notable complications associated with PDT. Photofrin is retained in the skin for approximately 6–8 weeks following infusion, causing significant photosensitivity. This can lead to significant sunburn that necessitates patients wear protective clothing and eye protection when exposed to sunlight. The tissue death occurring 2 days after treatment necessitates repeat bronchoscopy to remove desiccated tissue. In 7% of cases, tissue sloughing can result in significant airway obstruction causing life-threatening respiratory distress. Therefore a repeat bronchoscopy 48 h after PDT is essential to remove sloughed tissue. Bronchial stenosis has been reported if the treatment area overlaps with normal respiratory mucosa. While extremely rare, life-threatening hemoptysis can occur if the target area is <1 cm from a major mediastinal vessel.
PDT is employed in two clinical scenarios, one with curative intent for carcinoma in situ and the other for palliation of symptoms in obstructive malignant disease. In a prospective study of 175 lung cancer patients from 1982 to 1996, McCaughan and Williams used PDT to treat 16 patients with stage I disease, 9 patients with stage II disease, 106 with stage III, and 44 patients with stage IV disease. Most patients had squamous cell carcinoma of the airway. The authors applied energy of 400 J/cm diffusing fiber for trachea and main bronchi, 300 J/cm for lobar bronchi, and 200 J/cm for segmental bronchi. The median survival of all patients in the study was 7 months, but when assessing each subgroup, stage I survival was not reached, stage II was 22.5 months, stage IIIA 5.7 months, stage IIIB 5.5 months, and stage IV 5 months. Three patients with squamous cell carcinoma in situ had complete responses (CRs) with no evidence of disease at 8, 74, and 121 months. The disease-free survival for stage I disease was 93%.
In a different study from Japan, a total of 204 patients with 264 centrally located early stage lung cancer lesions underwent PDT between February 1980 and February 2005. Two hundred and fifty-eight of the lesions were squamous cell carcinomas, 185 were clinical stage 0, and 79 were clinical stage I. Tumor dimension was less than 1 cm in 180 lesions, between 1 and 2 cm in 50 lesions, and more than 2 cm in 34 lesions. For the 56 tumors <0.5 cm, CR was 94.6%, lesion 0.5–1 cm CR was 93.5%, 1–2 cm CR 80%, and >2 cm CR 44.1%. The distal margin of the tumor was visible on 203 of the lesions, which corresponded to a CR of 91.6%. Importantly, though, for lesions <1.0 cm the CR of 92.8% corresponded with a 5-year survival rate of 57.9%. The authors of the study attribute this to the study participants’ frailty, as they were not deemed surgical candidates and the vast majority of patients died from other diseases associated with their poor cardiopulmonary reserve.
Regarding palliation of symptoms, Moghissi and colleagues recruited 100 patients with advanced inoperable lung cancer (73% stage IIIa, 10% stage IV) between May 1990 and May 1997. The study was set up to record symptoms (dyspnea, cough, and hemoptysis) and performance status using the World Health Organization (WHO) scale. The WHO scale is arranged from 0 (able to carry out all normal activities without restriction) to 4 (completely disabled). Patients (59% squamous, 24% adenocarcinoma) underwent PDT to their airway tumor following Photofrin injection. Follow-up of these patients was completed every 6–8 weeks for 1 year and then in 3–6-month intervals. At these visits data were collected. Pre-PDT treatment, 43 patients had a WHO scale of ≤2 and 54 patients had a WHO scale of ≥2. Six to eight weeks following PDT treatment, 87 patients had a WHO scale of ≤2 and 10 patients had a WHO scale of ≥2. Similarly forced expiratory volume in the first second of expiration (FEV 1 ) increased by 0.28 L following PDT and forced vital capacity (FVC) increased by 0.43 L. While multivariate analysis demonstrated that only performance status was statistically significant for survival, there was a significant improvement in functional status following treatment with PDT.
PDT elevated the field of therapeutic bronchoscopy to the curative domain. In the right patient population, particularly patients with <1 cm length squamous cell carcinoma in situ, there is a ~90% chance of CR. While tumors are ideally centrally located, there is increasing interest in using available technology to provide treatment to distal airways. PDT also has applications for malignant central airway obstruction, often used in tandem with other usual treatment modalities such as chemotherapy and radiation. Newer tumor-specific photosensitizers are being developed with fewer side effects and hopefully more efficacy. PDT is a technology that has continued to evolve since 1982 and is anticipated to remain in the armamentarium of interventional pulmonologists worldwide.
Endobronchial lesions can develop from primary lung cancer or metastatic disease leading to airway obstruction. Most of these patients are not candidates for surgical resection and are likely to experience shortness of breath, hypoxemia, hemoptysis, and recurrent postobstructive pneumonia. Airway obstruction due to benign conditions like mucus plugging, blood clot impaction, foreign body aspiration, and benign strictures can also lead to similar symptoms. The use of cryotherapy for immediate recanalization of the airway by debulking endobronchial lesions is described elsewhere. However, cryotherapy has a vital role as delayed therapy to restore the patency of airways for treatment and palliation purposes. This section summarizes the critical aspects of using cryotherapy as a delayed endobronchial ablative treatment and cryoextraction to remove foreign bodies, mucus plugs, and blood clots obstructing the airways.
The use of severely low temperatures to treat tumors was first described as early as 1851 by James Arnott for a lesion in the breast. Cooper and Lee subsequently introduced the first closed-tip cryoprobe using liquid nitrogen in 1961; its first endobronchial use was by Gage using a rigid cryoprobe. A flexible cryoprobe was developed in 1994. The cryoprobe gets cold to extremely low temperatures. It captures the cooling effect of the rapid expansion of a gas that has been liquefied under high pressures. This phenomenon is also known as the Joule-Thomson effect. Cryotherapy is applied to tissue through multiple approaches: percutaneous, thoracic, endobronchial, and so on. It has been shown to treat or palliate unresectable cancers and can potentially increase long-term survival. Endobronchial cryotherapy is suggested for the treatment of endobronchial tumors and removal of foreign bodies and blood clots obstructing airways in the European Respiratory Society/American Thoracic Society guidelines (2002) and American College of Chest Physician Guidelines in 2003.
Mechanism of Action
Cryotherapy induces tissue destruction through intracellular and extracellular cryocrystallization. Through the specially designed cryoprobe, extremely low temperatures can be applied to a local area leading to the initiation of these destructive events. Intracellular ice crystal formation leads to damage to intracellular organelles like mitochondria and endoplasmic reticulum, whereas extracellular ice crystallization leads to intracellular dehydration and cell death. Mazur described the cell death mechanism by cryotherapy; 90% cell death can be achieved if tissue is cooled quickly to −40°C at the rate of −100°C per minute. Lower temperatures and repeat freeze-thaw cycles contribute incrementally to cell death. Also, cryotherapy leads to microthrombi formation in the surrounding vasculature, hastening cell death and selectively targeting the hypervascular tumor tissue. For the same reason, tissues with higher water content are more sensitive to cryotherapy (granulation tissue, tumor, nerves, endothelium), while bronchial cartilage is relatively spared from tissue destruction, along with fibrosis, nerve sheath, and connective tissue.
Immediate relief of an obstructed airway from foreign bodies, blood clots, and mucus plug can also be obtained through cryotherapy and is based on a different mechanism of action. Under bronchoscopic guidance, the cryoprobe is put in direct contact with the culprit obstructing tissue/foreign body and is activated. As the cryoprobe freezes to extremely low temperatures, it adheres to the adjacent tissue. The cryoprobe is then removed en bloc with the bronchoscope. Large fragments of mucus, organized blood clots, and some foreign bodies can be removed with this technique, which may otherwise not have been possible through flexible bronchoscopy alone.
Indications and contraindications to performing endobronchial cryoablation or cryoextraction can guide patient selection and should be reviewed before planning these procedures.
Intraluminal tumors of histology-proven malignancies causing endobronchial obstruction.
Treatment of low-grade endobronchial malignancies like carcinoid tumors that are otherwise unresectable.
Granulation tissue growth leading to airway obstruction.
Retrieval of foreign objects from central and segmental airways. Objects with more water content like certain food materials and tissue are more amenable to cryoextraction as opposed to metallic objects, plastics, teeth, bone material, etc.
Retrieval of organized blood clot/thrombus and mucus plugs from the airways, not cleared with therapeutic suctioning and causing respiratory compromise or risk of postobstructive pneumonia.
Lack of expertise or training in performing endobronchial cryotherapy.
Presence of bleeding diathesis, thrombocytopenia <50 × 10 9 , use of clopidogrel and newer antiplatelet agents, and anticoagulant therapy would present a high risk of bleeding complications with endobronchial cryotherapy as well as any endobronchial intervention.
Any contraindications to undergoing the bronchoscopy procedure itself.
For delivery of cryotherapy for any of the aforementioned indications, a combination of the below three types of equipment is needed ( Fig. 9.6 ):
Cryosurgery device or cryoprobe: The flexible cryoprobe comes in two operating diameters: 2.4 mm and 1.9 mm. Its length is 90 cm, and the length of the cooling tip is 7 mm (ERBE USA, Inc.; Marietta, GA, USA). Besides the flexible probe, rigid and semirigid cryoprobes are also available but are less commonly used. The rigid and semirigid cryoprobe can only be used with a rigid bronchoscope. Their advantage is a short thawing phase of the probe leading to a faster procedure; however, this can also decrease the extent of cellular injury achieved, and hence use of the flexible probe may be overall preferred.
Cryogen or cooling agent: The cryogen is stored in a liquefied state under high pressure in a cylinder on the cryo machine. Nitrous oxide, nitrogen, and carbon dioxide are the most commonly used cryogens. Nitrous oxide is reported to cool the cryoprobe tip to −89°C, whereas the carbon dioxide cools to −79°C within a few seconds. The cylinder connects to the cryoprobe, and, when activated, cryogen is released through a transfer line to the cryoprobe tip. The tip has a chamber for ingress and egress of the gas leading to its rapid freezing. A regulator located on the cryo machine controls the rate of freezing of the cryoprobe by regulating the flow of the cryogen ( Fig. 9.6 ).
The delivery device: A flexible fiberoptic bronchoscope or a rigid bronchoscope can be used to deliver endobronchial cryotherapy. Using the flexible bronchoscope does not always require general anesthesia. It can also reach the distal bronchi and upper lobes, which is otherwise difficult with a rigid bronchoscope. Flexible fiberoptic bronchoscopes with a large working channel of 2.8 mm or more allow the cryoprobe to be inserted easily and also leave the ability to apply some suction if needed ( Fig. 9.7 ).