Cancer of the pleura is a virulent and lethal malignancy. Primary tumors of the pleura are rare, whereas metastatic tumors, often in the form of malignant pleural effusions, are quite common. Primary tumors of the pleura, malignant pleural mesothelioma being the most common, are typically associated with a life expectancy of less than a year. Metastatic cancers to the pleura, including non–small-cell lung cancer (NSCLC), represent stage IV disease and usually coincide with the most adverse prognosis for the primary cancer that has spread to the pleura.

The most common form of treatment for pleural cancers is systemic therapy and/or palliative care, since the majority of pleural cancers represent metastatic disease. Surgery is not typically considered an effective treatment because of the essentially impossible task of achieving a true negative margin for these cancers that coat every surface of the chest cavity. In an investigational capacity, however, surgery has become the cornerstone of highly aggressive multimodal treatment plans in selected patients, and the most widespread application in malignant pleural mesothelioma.

With the expectation that microscopic disease will remain after even the most aggressive surgical resections, one approach has been to combine an intraoperative adjuvant therapy with systemic therapy and, sometimes, adjuvant external beam radiation. The intraoperative adjuvant therapies include the following: chemotherapy, with or without hyperthermia, heated povidone iodine, radioisotopic radiation, intraoperative photon radiation, and photodynamic therapy (PDT).¹ This chapter focuses on the combination of surgery and PDT and the application of this technique in malignant pleural mesothelioma.

PDT is a technique for killing tumors which uses a photosensitizer that is activated by visible light. It has been observed that photosensitizers are preferentially taken up by, or retained in, tumor cells.^2,3 Once inside the cells, the photosensitizer is activated by a laser light with a wavelength specific to the sensitizer’s absorption spectrum. Activation of the photosensitizer in the presence of oxygen results in the production of excited species of oxygen capable of inducing cell death. Cell death occurs by apoptosis or from direct destruction of certain cellular elements.^4,5 In addition, PDT may result in neovascular damage that may compromise the tumor’s blood supply.⁶ Finally, when PDT is used to treat cancer, it appears to enhance the host’s immune response to the tumor.^7,8

In addition to the presence of oxygen, the items needed to perform pleural PDT include the photosensitizer, a light source, and a dosimetry system. PDT is a dose-dependent treatment. That is, without light activation there is no effect on cells that contain the photosensitizer. The overall effect of PDT increases with the amount of activating light delivered. Although photosensitizers may demonstrate some selectivity for neoplastic cells, they also partition into normal tissues and will cause some degree of damage to those tissues when exposed to light. This is critical, especially for pleural PDT, as injury to any structure in the chest can occur absent meticulous attention to light dosimetry.

Photosensitizers

The majority of experience with pleural PDT has been with two photosensitizers, Photofrin and Foscan. Photofrin (dihematoporphyrin derivate) was the first commercially available photosensitizer and has its major excitation wavelengths in the UV region (200–450 nm), the green region (510 nm), and a small absorption peak in the red (630 nm) region of the light spectrum. Meta-tetrahydroxyphenylchloride (Foscan®) is the second drug that has been used for treating mesothelioma.² It has major absorption peaks in the UV (200–450 nm) green regions (520 nm), with the highest peak in the red region at 652 nm. Although the shorter wavelengths have higher energy, red light is used for greater tissue penetration, which can be up to several centimeters depending on the absorption and scattering characteristics of the tissue.

Both of these photosensitizers are administered intravenously, preoperatively. As stated previously, photosensitizers may demonstrate some element of selectivity, but will ultimately sensitize all tissues, including the skin. As a result, cutaneous photosensitivity is the primary toxicity associated with administering a photosensitizer.^9,10

Laser Equipment

To treat large surface areas with PDT, high-power light sources are required. In general, it is necessary to use a laser to supply light at the appropriate wavelength and intensity. Tunable dye lasers, pumped by a larger green light laser with fixed wavelength, are commonly used to produce red light in the 7 W range. These lasers have the advantage of possessing dye modules that can be interchanged to permit production of a broad spectrum of wavelengths. The disadvantage is that they are relatively large and require high-power supplies and water-cooling systems. Recently developed diode lasers are more portable and have power outputs up to 6 W (in the red light waveband). They do not require the use of high-power supplies or water-cooling systems, but have the disadvantage of being fixed at a single wavelength.

Dosimetry

Although photosensitizers may preferentially migrate to tumor tissues, it should be assumed that all tissues are photosensitive. As a result, any structure that is illuminated can be injured. It is crucial, therefore, not to overdose normal tissues with light. Some investigators rely upon “calculated” light doses.^11,12 On the basis of experiments which demonstrate that the measured and calculated light doses may vary widely owing to the unpredictable reflection and refraction patterns of light in vivo,¹³ we believe that light dosing should not be empiric and one should rely on measured dosimetry. Consequently, light sensors are placed at strategic positions within the hemithorax and fed into a real-time dosimetry system that has a separate channel for each sensor. During PDT, the light source is moved around the chest cavity until each sensor has measured the desired dose of light.

Currently two types of sensors are used: flat and isotropic. The flat sensors¹⁴ underestimate the light dose delivered to the tissue surfaces in comparison with isotropic detectors.¹⁵ If the type of sensor or photosensitizer is changed, measurements must be made to determine the conversion factor between the sensors or safety studies to determine the safe maximal tolerated dose.¹⁶

Some investigators fill the hemithorax with diffuse intralipid solution to help scatter light as the light source is moved around the chest cavity.^14,17 This is our preferred method for light delivery regardless of the debulking technique. It assures that there is no shielding of tissue by pooled blood and also permits direct manipulation of the costophrenic recesses, the most difficult areas in which to achieve good light delivery. Others have focused on integral illumination by using a bulb fiber and no light-diffusing medium.¹³ This technique is only applicable after a pneumonectomy. In the latter technique, a transparent sterile bag is placed in the chest cavity following pneumonectomy and filled with warm saline to facilitate flattening and expansion of the chest cavity structures. After partial closure of the surgical wound, a single spherical bulb fiber is placed in the center of the bag to allow integral illumination of the entire cavity and enhance the reflection of light. This technique is not compatible with a lung-sparing procedure and may not be applicable if it does not appear that the bag will expand all crevices in the hemithorax. We abandoned this technique when we found that blood was pooling under the bag and preventing light from reaching those areas.

Overview

The concept behind the combination of surgery and PDT for pleural malignancies is that surgery is used to achieve a macroscopic complete resection and PDT is performed after the resection as an intraoperative adjuvant therapy in an effort to treat the residual microscopic disease.^18–21 The two options for achieving a macroscopic complete resection include extrapleural pneumonectomy (Chapter 122) and radical pleurectomy (Chapter 121).

Extrapleural pneumonectomy is defined as the en bloc removal of the lung, parietal pleura, diaphragm, and pericardium. Typically, both the diaphragm and pericardium are reconstructed with prosthetic patches. This operation has the advantage of being standardized with respect to both name and technique. It is almost certainly the technique that results in the least amount of residual microscopic disease, that is, the most complete and reproducible macroscopic complete resection. Finally, without the lung in the chest, radiation can be used as an adjuvant therapy to treat the entire hemithorax.

Radical pleurectomy is a more nebulous operation which, even in the best of hands, almost certainly leaves behind more microscopic disease than an extrapleural pneumonectomy. There is essentially no standardization of this operation and, in fact, the procedure appears in the literature under a multitude of names including pleurectomy, decortication, pleurectomy-decortication, radical pleurectomy-decortication, radical pleurectomy and extended pleurectomy. The intent of the operation also varies, from a palliative debulking of some gross disease to a macroscopic complete resection. This tremendous variability in every aspect of the procedure, including nomenclature, makes it difficult to compare published case series. Finally, the timing of the decision to perform the operation is also variable, ranging from an intraoperative decision based upon intraoperative findings to a preoperative plan. In the former situation, either the bulk of the cancer or the degree of involvement of the cancer with the pulmonary fissures is often cited as the deciding factor as in whether or not the lung can be saved.

For the purposes of the ensuing discussion, radical pleurectomy is the term that we use to describe a lung-sparing operation aimed at achieving a macroscopic complete resection. The goal of each procedure is to save the lung and, if possible, the phrenic nerve and as much of the pericardium and/or diaphragmatic musculature as possible, while still achieving a macroscopic complete resection. Depending upon the degree of invasion, it usually is not necessary to reconstruct the diaphragm. We have found this to be true for the pericardium as well, since the presence of the lung is sufficient to prevent cardiac herniation/torsion. In our hands, radical pleurectomy is a procedure that is planned preoperatively, not an intraoperative decision based upon involvement of the pulmonary fissures, tumor bulk, or other factors.

Thus, with respect to the two types of surgery for malignant pleural mesothelioma, the advantages of extrapleural pneumonectomy include relative standardization and hence comparability of results, the best macroscopic complete resection, the ability to treat with adjuvant radiation and, in our hands, a more expeditious operation than radical pleurectomy. The disadvantages are the consequences of pneumonectomy and, potentially, the need for prosthetic reconstructions. The principal advantage of radical pleurectomy is preservation of the lung and, potentially, the decreased need for prosthetic reconstruction. Preserving the lung not only translates into the potential benefits of preserving quality of life and offering a surgery-based approach to patients who might not be candidates for pneumonectomy, but it may also allow the patient to undergo more aggressive treatment options for their inevitable tumor recurrence. The disadvantages of radical pleurectomy include the presence of more residual microscopic disease, lack of standardization and, in our hands, a longer operation with a more complex postoperative management than with extrapleural pneumonectomy. The ideal surgical approach remains an area of controversy. It may well be that no one approach is correct for every patient. The optimal operative strategy may well be related to the individual patient, characteristics of their particular tumor, and the selection of adjuvant therapies that are going to be used in combination with surgery.

We have performed both extrapleural pneumonectomies and radical pleurectomies for mesothelioma in combination with intraoperative PDT. In a pilot study that compared the outcomes of these two surgical approaches, we found that the patients who underwent radical pleurectomy had longer overall survival compared with patients who underwent pneumonectomy (Fig. 124-1A), despite essentially no difference in disease-free survival (Fig. 124-1B). The term “MEPP” was used in the study cited in Figure 124-1 as the operation involving pneumonectomy preserved the diaphragm, pericardium, and phrenic nerve. The currently accepted definition of extrapleural pneumonectomy is en-bloc resection of the parietal and visceral pleura with the ipsilateral lung, pericardium, and diaphragm. In cases where the pericardium and/or diaphragm are not involved by tumor, these structures may be left intact.²²

On the basis of this pilot study, we switched exclusively to radical pleurectomy as our surgical approach to malignant pleural mesothelioma. We still, however, will perform an extrapleural pneumonectomy in combination with PDT for NSCLC with pleural dissemination (stage IVa). Although the era of targeted therapies has provided more treatments for patients with this disease, this approach has shown promise as an aggressive option for patients with this cancer.²³ In either case, whether the lung is taken or spared, the light precautions taken during surgery and the performance of PDT are identical.

Patient selection for these procedures takes place in the forum of a multidisciplinary tumor board-type conference with disease limited to one hemithorax as the principal oncologic criteria for consideration as a surgical candidate. Eligible and interested patients undergo an extensive radiographic staging workup and ultimately undergo an invasive staging procedure including bronchoscopy and laparoscopy to rule out radiographically occult metastases. While the presence of ipsilateral mediastinal lymph node metastases (N2 disease) is not currently viewed as an exclusion criterion for radical pleurectomy for mesothelioma, as it is for extrapleural pneumonectomy, this does correlate with a decrease in overall survival and we have started to routinely include endobronchial ultrasound-guided biopsy (EBUS) staging as part of our preoperative evaluation. Contralateral thoracoscopy, to rule out contralateral pleural disease, and mediastinoscopy or EBUS, to rule out N3 disease, are used on a case-by-case basis as dictated by the imaging studies and clinical suspicion. From a safety perspective, the selection criteria are the same as would be used for any major thoracic operation, such as a formal decortication or pneumonectomy, with an added emphasis on nutritional parameters. The PDT superimposes a significant metabolic demand, and malnutrition serves as an exclusion criteria. As part of the informed consent disclosures, it is made clear to all patients that the procedure is investigational and, in addition to the risks of the surgery, there are the superimposed risks of PDT; primarily, cutaneous photosensitivity and a higher incidence of postoperative atrial fibrillation, deep venous thromboses (but not pulmonary embolism), and persistent air leaks in radical pleurectomy patients.

Photosensitizer and Light Precautions

Before surgery, the patient receives the photosensitizer as an outpatient. The patient becomes immediately light sensitive. Therefore, patients should be instructed to bring sunglasses and wear appropriate clothing to cover or shade all exposed skin. With adequate patient education, we have not experienced any problems with sunburning before or after surgery. Once the patient arrives for surgery, hospital light precautions are initiated. This includes no exposure to sunlight through windows or intense overhead lights (fluorescent lights are fine) and probe rotation or spot-checking pulse oximetry. In the operating room the overhead lights and surgical headlights are passed through yellow filters. Yellow represents the portion of the visible light spectrum where the photosensitizers absorb less light, but these are not turned on until the incision is shielded with towels and all skin is protected from these intense light sources (see Fig. 124-2).

Technique of Radical Pleurectomy

General Approach and Strategy

Over the years we have tried multiple techniques in an attempt to develop a standardized approach to radical pleurectomy. What follows is a description of our current iteration of this procedure. The general strategy that has resulted in the most reproducible results is to mobilize the entire cancer from the hemithorax, such that it is tethered solely to the lung, and then resect the entire visceral pleura, en bloc with the mobilized cancer. With the proviso that every one of these cancers is different and the surgeon must remain flexible in the approach, the typical order of dissection is bony hemithorax, posterior mediastinum, superior mediastinum, anterior mediastinum, diaphragm, and lung.

Preparation and Incision

Light precautions, as stated above, are taken from the time the patient receives the photosensitizer. Patients undergoing radical pleurectomy will need a central line with one port reserved for total parenteral nutrition, epidural catheter, ipsilateral radial and femoral arterial lines and a nasoenteric tube, peripheral venous access, and a Foley catheter. Once it is confirmed by bronchoscopy that the nasoenteric tube is not in the lungs, it is our routine to give 60 mL of heavy cream spiked with an amp of methylene blue to aid the detection of injury to the thoracic duct during the course of the surgery. The patient is then placed in the lateral decubitus position and a thoracotomy incision is created under operating room fluorescent lights only. The latissimus is divided, but we are usually able to preserve and retract the serratus muscle. Once the chest wall layer is approached, the towels can be sewn to the muscle fascia to shade the skin, and the overhead and surgical headlights can be activated. If there is a rib interspace, the extrapleural plane is approached through the sixth interspace. If the interspace is contracted to the point of rib overlap, or the patient has had previous surgery through the sixth interspace to preclude entry, the seventh rib is removed and the extrapleural plane is approached through the bed of the resected seventh rib.

Chest Wall/Posterior-Superior Mediastinal Mobilization

The initial portion of the operation is the same whether the surgeon is planning to perform a radical pleurectomy or extrapleural pneumonectomy. The first step of the mobilization is to free the cancer from the bony hemithorax, followed by the posterior and superior mediastinum. The plane is identified and entered adjacent to the incision. It is developed bluntly, as much as possible. Blunt finger dissection, working a broad front, causes cleavage in the correct plane. Sharp dissection is more likely to leave behind gross tumor. The argon beam coagulator or Aquamantys® is good for cauterizing the chest wall, from which capillary oozing can lead to significant blood loss. Dissecting the chest wall is the safest portion of the operation and provides a good opportunity for the surgeon to get a sense of how the tumor is interacting with the tissues (Fig. 124-3A,B).