Malignant pleural effusion is usually the consequence of an advanced cancer that has spread to the pleura. The presence of a malignant pleural effusion represents an ominous finding for the patient and a formidable challenge for the treating physician. Depending on the nature of the underlying malignancy and applicable treatments, the presence of a malignant effusion commonly portends a survival measured only in months. Malignant effusions are most commonly a manifestation of advanced cancers that have spread to the pleura, although they may result from primary cancers of the pleura. Primary cancers of the pleura are very rare. Pleural mesotheliomas comprise the majority of these unusual tumors. Advanced cancers of the lung, breast, ovary, or various lymphomas account for 75% of all malignant effusions. Most of the remaining malignant pleural effusions represent metastatic spread of a variety of gastrointestinal and genitourinary malignancies, tumors of other solid organs, or the spread of cancers of unknown origin.^1,2

The most common role for the surgeon in treating malignant pleural effusions is palliation. Depending on many factors, this can take the form of thoracentesis, pleurodesis, external drainage with a long-term drainage catheter, or internal drainage with a pleuroperitoneal shunt (see Chaps. 100 and 101). Given that malignant pleural effusions usually represent some form of metastasis, any intervention beyond palliation most commonly involves a systemic approach.

When surgery is to be performed with "curative intent" for a malignant pleural effusion, it is virtually without exception part of a multimodality treatment approach. The reason for this is that it is nearly impossible to achieve true negative margins when resecting the pleura, even with an aggressive operation such as extrapleural pneumonectomy (EPP; see Chap. 103). Achieving negative margins for pleural malignancies is analogous to attempting to scrape paint off a brick wall and then subjecting the wall to microscopic examination To the naked eye, the wall may appear pristine, but examined under a microscope, there almost certainly would be residual paint. With pleural surgery, the microscopic "paint chips" represent viable cancer cells. Any attempt at a curative resection for malignant pleuritis without complementary modalities to address the problem of residual microscopic disease almost certainly will be met by an extraordinarily high rate of local recurrence. The modalities used most commonly to treat the pleural space locally are hemithoracic radiation, hyperthermic intraoperative chemotherapy lavage (see Chap. 104), and photodynamic therapy (PDT), a light-based cancer treatment. Radiation of the hemithorax mandates removal of the lung to avoid radiation toxicity to the lung. Chemotherapeutic lavage and PDT can be performed intraoperatively and do not necessarily mandate lung removal.

For the purposes of this chapter, the term malignant pleuritis will be used to include all conditions ranging from a malignant pleural effusion with no visible or palpable pleural tumor to a gross, bulky pleural cancer. As a general rule, I would only consider PDT for malignant pleuritis if it were part of a treatment strategy that would leave the patient without any site of untreated cancer. The cancers that lend themselves to this situation are those that originate in one hemithorax, most commonly mesothelioma or non-small cell lung cancer (NSCLC) with pleural dissemination. Although there is fairly extensive experience with pleural PDT, primarily for mesothelioma, it is still considered an experimental treatment.

PHOTODYNAMIC THERAPY

PDT is a technique for destroying tumor cells that relies on the preferential uptake of photosensitive compounds known as photosensitizers.^3,4 Once inside the tumor cell, the photosensitizer is activated by laser using a light wavelength specific to the sensitizer's unique absorption spectrum. Activation of the photosensitizer in the presence of oxygen produces excited oxygen species that are capable of inducing cell death. Cell death occurs either by apoptosis or by direct destruction of certain cellular elements.^5,6 In addition, PDT is capable of causing neovascular damage that may compromise the tumor's blood supply.⁷ PDT also appears to enhance the host's immune response to the tumor.^8,9 Although PDT has been approved for use by the Food and Drug Administration in non-small cell lung cancer and cancer of the esophagus, its use in mesothelioma is still undergoing clinical trial, and hence it is considered experimental and only available to patients on protocol.

In addition to the presence of oxygen in room air, the items needed to perform pleural PDT include the photosensitizer, a light source, and a dosimetry system. PDT is a dose-dependent treatment. The overall effect of the treatment increases with the amount of activating light delivered to the target. Without light activation, the sensitizer has no effect on cells. 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 if they are exposed to light. It is critical to bear this in mind, especially for pleural PDT, because injury to any structure in the chest can occur absent meticulous attention to light dosimetry.

Photosensitizers

The majority of experience with pleural PDT in malignant pleural mesothelioma has relied on two photosensitizers, Photofrin and Foscan. Dihematoporphyrin derivative (Photofrin) was the first commercially available photosensitizer. It has three major excitation wavelengths located in the ultraviolet (200–450 nm), the green (510 nm), and a small absorption peak in the red (630 nm) regions of the light spectrum. meta-Tetrahydroxyphenylchloride (Foscan) also has been used to treat mesothelioma. It has major absorption peaks in the ultraviolet (200–450 nm) and green (520 nm) regions, but the highest peak is in the red at 652 nm.³Although the shorter wavelengths have higher energy, red light is used for its greater depth of tissue penetration. Red light penetrates tissue in the range of several millimeters up to a centimeter depending on the absorption and scattering characteristics of the tissue. Green light, by comparison, penetrates only a few millimeters. Both these photosensitizers are administered intravenously preoperatively. Because uptake is not limited to neoplastic cells, cutaneous photosensitivity is the primary toxicity of administering a photosensitizer.

Laser Equipment

High-power light sources are required to treat large surface areas with PDT. 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 fixed-wavelength green light laser are used commonly to produce red light in the 7-W range. The advantage of the dye laser is that the dye modules can be interchanged, permitting a broad spectrum of wavelengths. The disadvantages include their relatively large size and need for high power supplies and water cooling systems. Diode lasers have been developed that are more transportable and have power outputs of 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 tumor tissues may be more sensitive to photosensitizers, it should be assumed that all tissues are photosensitive. As a result, all structures that are illuminated can be injured. It is crucial, therefore, to avoid overdosing normal tissues with light. Some investigators rely on "calculated" light doses.^10,11 Experiments have demonstrated, however, that the measured and calculated light doses vary widely as a result of unpredictable reflection and refraction patterns in vivo. For this reason, we believe that light dosing must be empirical and rely on measured dosimetry¹² (Fig. 105-1). 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 (Fig. 105-2). During PDT, the light source is moved within the chest cavity until each sensor measures the desired dose of light (Fig. 105-3).

The two types of sensors currently in use are the flat and isotropic sensors. The flat sensors underestimate the light dose delivered to tissue surfaces, whereas spherical isotropic detectors do not.^13,14 Again, the safe dose of light must be determined empirically, and any exchange of sensors would require a predetermined conversion factor. Owing to the extraordinary risk of injury by an overdose of light in the chest, the use of a new photosensitizer requires safety studies to determine the safe maximal tolerated dose (MTD).

Some investigators fill the hemithorax with diffuse intralipid solution to help scatter light as the light source is moved around the chest cavity.¹³ This is our preferred method for light delivery regardless of the debulking technique because 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 ensure good illumination (Fig. 105-4). Others have focused on integral illumination by using a bulb fiber without use of a light-diffusing medium.¹² This technique is applicable only if the lung has been surgically resected. In this technique, a transparent sterile bag is placed in the chest cavity after 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 permit integral illumination of the entire cavity and to 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 into all crevices in the hemithorax. We abandoned this technique when we found that blood was pooling under the bag, which potentially could shield those areas from light.

SURGICAL APPROACH

Overview

The rationale for combining surgery and PDT for malignant pleuritis is straightforward. The surgery is used to debulk all gross disease, whereas the PDT is used to treat the residual microscopic disease. Through this combination, one can achieve an MCR. The surgical debulking procedures include a lung-sparing pleurectomy (see Chap. 102) or an EPP (see Chap. 103). Although a challenging operation, EPP is the most direct and effective way to achieve complete pleural debulking. This operation, however, is likely to have a significantly higher morbidity and mortality than lung-sparing pleurectomy. In addition, pneumonectomy is likely to have a greater negative impact on the patient's quality of life. As a result, we are biased in favor of performing a lung-sparing procedure, whenever possible, followed by intraoperative PDT. The goal of every debulking procedure is the same—to conclude the operation with no visible or palpable disease remaining in the chest.

Malignant Effusion without Visible Gross Disease

Occasionally, a patient will have a malignant effusion with no detectable gross disease. In this circumstance, the procedure may commence thoracoscopically. If under this magnified approach there is truly no evidence of gross disease, we perform a thoracoscopic parietal pleurectomy of the bony hemithorax, ensure that the natural fissures are well developed to prevent light shielding, insert the standard seven light detectors through the thoracoscopy incision, and administer the PDT thoracoscopically (Fig. 105-5). We have treated a patient with primary ovarian cancer that recurred as an isolated malignant pleural effusion in this fashion. Although our experience remains anecdotal, the patient was treated thoracoscopically and remained disease-free in her chest, even when she returned with a peritoneal recurrence 2 years later. We also have treated several patients with breast cancer in a similar manner. Unfortunately, patients for whom this appears to be a reasonable treatment and who are suitable for a thoracoscopic approach are few in number.

Patients with an Element of Gross Pleural Disease

It is more common for patients to present with moderate evidence of pleural disease. Before the patient undergoes surgical debulking and intraoperative PDT, it is our practice to perform an extensive metastatic workup, which includes a brain MRI, CT scan of chest/abdomen/pelvis, and bone scan or PET scan. Any suspicion of pericardial, cardiac, or great vessel invasion is further evaluated with MRI studies and/or esophageal echocardiography. Invasive staging with a bronchoscopy, esophagoscopy, and laparoscopy with peritoneal washings and biopsy is also performed routinely for patients with mesothelioma and for any other patient in whom there is suspicion of radiographically occult disease. Mediastinoscopy can be used to stage the paratracheal lymph nodes and should be used if the results affect enrollment in the protocol undergoing clinical trial. Before surgery, every patient is evaluated for cardiac and pulmonary function. If no metastatic disease is detected, the patient receives the photosensitizer at the appropriate time interval and is brought to the OR for surgical debulking and PDT.

Incision and Exposure

Standard double-lumen endotracheal intubation is performed, and the patient is placed in the lateral decubitus position. Pulse oximeters use a red light probe capable of activating photosensitizers and, consequently, can cause burns to the nail bed. To avoid this complication, the operator rotates the oximeter probes between his or her fingers every 15–30 minutes.

Debulking Surgery

Before the overhead operating lights and surgeons' headlights are turned on, a posterolateral thoracotomy incision is created using only the fluorescent room lights for illumination. If only minimal disease is anticipated, the chest can be entered through the fifth, sixth, or seventh interspace depending on where the surgeon anticipates the greatest amount of dissection will be necessary. A serratus-sparing thoracotomy is performed if it affords an adequate view. Otherwise, portions of the serratus that need to be elevated are dissected from their origin. It is common for the costophrenic recess to bear most of the disease, and in this circumstance, removal of the seventh rib and a generous thoracotomy with more extensive mobilization of the serratus muscle are helpful. Previous biopsy sites are excised if the patient is undergoing surgery for mesothelioma or if the patient is undergoing surgery for another tumor and there is palpable tumor in any of the previous incisions.

Since the patient is already light sensitive, only fluorescent overhead lights can be used while the incision is created. Once the soft tissue portion of the incision is made, the skin is shielded by sewing blue towels to the edge of the wounds. After every square centimeter of exposed skin has been covered with drapes and towels, the headlights and overhead lights may be turned on without fear of causing cutaneous burns. The overhead OR lights and surgeon's headlamp are covered with yellow filter paper to reduce photosensitizer activation (Fig. 105-6).

Although PDT can be expected to penetrate tissue to a depth of at least several millimeters, it should be the goal of the surgeon to have no visible or palpable tumor remaining at the conclusion of the debulking procedure. It is our bias to attempt at least partial-thickness preservation of both the pericardium and diaphragm to avoid tumor spillage into other body cavities regardless of whether a pneumonectomy or decortication is performed.¹¹ If the diaphragm and/or pericardium cannot be debulked macroscopically, those structures are left intact until light delivery and then are resected and reconstructed subsequently with the appropriate prosthetic patches. Those structures are left in place to avoid overdosing the underlying structures, such as the heart, with light.

Light Delivery

In addition to limiting blood loss, maintaining hemostasis facilitates light delivery by decreasing the amount of heme pigment available to absorb light. Both the argon beam coagulator and the bipolar cautery are very helpful for this purpose and are used frequently during the debulking portion of the procedure. The PDT is also hemostatic, and we have found that capillary level leaks from the chest wall commonly will stop as the light dose approaches 10 J/cm².

The distribution and total dose of light delivered are monitored with light detectors (Rare Earth Medical, West Yarmouth, MA) that have an accuracy of ±15%.^15,16 Seven probes are placed in the thoracic cavity at the following locations: apex, anterior sulcus, posterior sulcus, anterior chest wall, posterior chest wall, pericardium, and posterior mediastinum. The light dosimetry system (Clinical Physics Department, Daniel den Hoed Cancer Center, Rotterdam, The Netherlands) and light sensors are shown in Figs. 105-2 and 105-3.¹⁵ Light is delivered into the chest cavity via a flat cut fiber placed within a modified endotracheal tube sealed at both ends and filled with 10% intralipid solution. Laser light is generated using the KTP/532 Laser System pumping a Model 630 XP Dye Module (Laserscope, Inc. San Jose, CA). This system is capable of delivering 7 W of red light. During light delivery, the retractors are removed from the chest cavity to avoid shielding, and the hemithorax is filled with 0.1% intralipid solution. It is important for the chest cavity to be hemostatic because heme pigment absorbs light and will cause a significant and noticeable decrease in the fluence. We aspirate and replace the warm intralipid solution constantly throughout the procedure to facilitate light delivery (see Fig. 105-3). Photofrin is delivered 24 hours preoperatively at a dose of 2 mg/kg. We deliver the light to a measured dose of 30 J/cm² for flat detectors or 60 J cm² if we are collecting light with isotropic detectors. This 2:1 equivalent derives from a series of patients in whom both sets of detectors were sewn side by side during light delivery and demonstrated the superior light-collecting ability of spherical detectors.¹⁶ This also demonstrated the need to measure light because even having the ability to capture incident photons indirectly, which will activate the photosensitizer just like a directly incident photon, dramatically increases the detectable light in the chest.

CLINICAL STUDIES

Mesothelioma Treated with Pleural PDT

Most of the literature that addresses the combination of surgery and intraoperative PDT pertains to the treatment of mesothelioma. This stands to reason because mesothelioma is a disease looking for innovative treatments and is also less likely to be found outside the chest cavity compared with the many other causes of malignant pleural effusion.

The first studies that combined surgery and PDT were published in 1994.^10,13 Both studies used Photofrin. In 1998, a study was published of 40 patients along with a 6-year follow-up of those original patients.¹⁴ Patients were treated with pleurectomy alone (n = 28), with EPP (n = 7), or with combined pleurectomy and lobectomy (n = 5) to achieve optimal cytoreduction. The morbidity and treatment-related mortality for this series were 45% and 7.5%, respectively. Complications included atrial fibrillation (n = 15), sepsis (n = 11), prolonged ventilation (n = 10), and bronchopleural fistula (n = 3). In addition, five patients underwent reoperation for spontaneous splenic rupture, diaphragmatic dehiscence, esophageal perforation, empyema, and diaphragmatic hemorrhage. The three patients who died of treatment-related causes were excluded from the survival analysis, leaving 37 patients. The median survival and estimated 2-year survival were 15 months and 23%, respectively. However, when patients were categorized by disease stage, the median survival and 2-year survival for stage I and II patients were 36 months and 61%, respectively, compared with 10 months and 0% for patients with stage III and IV disease. The authors of this series concluded that surgical intervention and PDT yielded good survival results in patients with stage I or II pleural mesothelioma.

Another group performed a phase I study in 54 patients.¹³ A total of 12 patients could not be debulked to the prerequisite 5-mm residual tumor thickness and thus were excluded, leaving 42 patients for the study. The choice of surgical resection depended on the extent of the disease but was limited to five lobectomy-pleurectomies, 19 modified pleuropneumonectomies, and 18 pleurectomies. The illumination procedure was performed with real-time dosimetry using seven flat photodiodes. The MTD was declared as 30 J/cm² with a 24-hour dosing interval. Based on these results, the authors conducted a phase III study comparing maximal debulking surgery and postoperative cisplatin, interferon-2a, and tamoxifen immunochemotherapy with or without intraoperative PDT.¹⁶ The type of resection for patients assigned to PDT (n = 25) included 11 pleurectomies and 14 pneumonectomies compared with the group without PDT (n = 23), which underwent 12 pleurectomies and 11 pneumonectomies. There was one operative death secondary to hemorrhage, and each group had two bronchopleural fistulas. There were no differences in the median survival (PDT 14.4 months versus no PDT 14.1 months) or median progression-free time (PDT 8.5 months versus no PDT 7.7 months). Most of the patients had stage III or IV disease (n = 40), and this may explain why a better survival was not observed in the PDT group, because PDT is mainly a treatment for local control. It should be noted that this study did permit residual disease of 5 mm or less to be treated with PDT. Consequently, it is possible that the level of residual disease in this study was significantly different from "no visible or palpable disease" and that the residual tumor bulk was too large to treat effectively with PDT.

The first report of a second-generation photosensitizer being used for mesothelioma was with meta-tetrahydroxyphenylchloride in 1991.¹⁷ Later, the same group reported on eight patients with "thoracic malignancies" in 1996.¹⁸ The PDT was performed without real-time light dosimetry; therefore, only an estimate of the delivered light doses could be made. Of the eight patients treated, three patients suffered severe postoperative complications, including colonic perforation (n = 1), bronchopleural fistula (n = 1), and aspiration pneumonia (n = 1). Several patients succumbed from distant manifestations of mesothelioma. Whether or not the PDT resulted in local control was not reported.

A phase I–II study investigated optimal dose and toxicities of meta-tetrahydroxyphenylchloride for intraoperative PDT in resected mesothelioma.¹⁹ In this study, doses of Foscan were escalated while the illumination times and surgical procedures were kept the same. Twenty-four patients had pleuropneumonectomies, and the drug light interval was 4 days for most patients. The illumination was performed until a total fluence of 10 J/cm² was achieved at all sites. In this study, a total of 28 patients with performance scores of 0-1 Eastern Cooperative Oncology Group (ECOG) were entered. In two of these patients, a pleuropneumonectomy could not be performed owing to extrathoracic growth of the tumor. At the third dose level (0.15 mg/kg Foscan), dose-limiting toxicity was observed. Three patients died as a result of myocardial infarction (n = 1), bronchopleural fistula (n = 1), and incorrect placement of the isotropic detectors in the thoracic cavity (n = 1). This resulted in an overdose of light at the mediastinal structures, leading to an esophagopleural fistula. The median survival for all 28 patients was 10 months. The authors concluded that Foscan-mediated PDT could not be recommended without further improvements in the PDT technique and better patient selection.

Our group subsequently performed a phase I study investigating the toxicities and MTD of Foscan-mediated PDT and surgery in 36 patients with MPM.¹¹ Four different PDT cohorts were studied in a total of 26 patients who completed treatment. Seven patients were debulked with an EPP, and 19 were debulked with a lung-sparing pleurectomy and decortication.

The grade III-V toxicities observed during this phase I trial included atrial dysrhythmia (n = 13), transient ventricular dysrhythmia (n = 2), incisional third-degree burn (n = 1), esophageal perforation (n = 1), acute respiratory distress syndrome (n = 1), and pulmonary embolism (n = 1). There were no operative mortalities, but there were two deaths within 90 days among the 20 patients treated at the MTD. One patient had a pulmonary embolism and was appropriately anticoagulated and discharged home. At home, the patient developed massive upper gastrointestinal bleeding and expired. The second patient died of complications after an iatrogenic esophageal perforation during endoscopy for upper gastrointestinal bleeding. The established MTD was 0.1 mg/kg of Foscan injected 6 days before surgery in combination with 10 J/cm² of 652-nm light. The dose-limiting toxicity was a systemic capillary leak syndrome that resulted in two PDT-related mortalities. Fourteen patients were treated at the MTD without significant complications. The median progression-free and overall survival was 12.4 months for all 20 patients enrolled at the MTD. Only three patients treated at the MTD developed isolated local recurrences. These results were especially encouraging given that a significant proportion of patients had unfavorable histology and significant lymph node involvement, criteria that would exclude treatment by surgical protocols. Perhaps the most encouraging aspect of the trial was that 19 of the patients had undergone lung-sparing debulking procedures. There was a learning curve involved in performing this operation, and I was able to save the lung in 17 of the last 19 patients in the trial. Many of the patients had previously undergone pleurodesis, and this did not preclude a parenchymal-sparing operation. Tumor thickness also was not a factor once the technique was refined, and it was possible to release the lung from tumors that were several centimeters thick. On the basis of these results, we had intended to perform a phase II study that would have included systemic treatment to complement the excellent local control we observed. Unfortunately, the company producing Foscan changed management and did not wish to continue with mesothelioma research.

Non-Small Cell Lung Cancer with Pleural Dissemination (Stage IIIB) Treated with Pleural PDT

Another tumor that commonly presents with malignant pleuritis is non-small cell lung cancer (NSCLC). By definition, NSCLC with malignant pleuritis is a T₄ tumor, which renders these patients, at a minimum, stage IIIB. As with other etiologies of malignant pleuritis, there is no role for surgery alone. The median survival for patients with stage IIIB NSCLC by virtue of pleural dissemination has been reported to range from 2 months to greater than 1 year but is generally considered to be within the 6- to 9-month range.^20–22 The survival rate for this subset of stage IIIB patients is so poor that it has been suggested that this disease should be upstaged to stage IV.²³ Surgery appears to have little impact on survival and is accompanied by local failure rates as high as 90%.^24–28

Drawing on our experience with PDT for pleural mesothelioma, we crafted a trial for these NSCLC patients.²⁹ Patients were treated with a standard-of-care approach and systemic therapy and then were restaged to ensure that there was no new evidence of disseminated disease beyond malignant pleuritis. The patients then received Photofrin, 2 mg/kg, 24 hours preoperatively and underwent pleural debulking and pulmonary resection of their primary tumor. The lung operation entailed the appropriate anatomic resection, which ranged from segmentectomy to pneumonectomy. The protocol for pleural debulking and intraoperative PDT was the same as described for mesothelioma.

The purpose of the trial was to study local control at 6 months and to determine if there was any impact on survival compared with historical controls. Our preliminary report comprised 22 patients who were enrolled in the study. Of those 22 patients, 17 underwent complete debulking and intraoperative PDT. Two patients were unresectable, one from undetected cardiac involvement and one from undetected intraperitoneal involvement. Three patients underwent incomplete pleural debulking because of occult esophageal or great vessel invasion. Of the 15 patients assessable at 6 months, there was local control in 11 (73%). The median overall survival for all 22 patients was 21.7 months.

In a follow-up assessment that included 8 additional patients and longer follow-up, the median survival for all 30 patients was 26.5 months. Of note, 22 patients underwent pneumonectomy, and all of them had N₂ disease in addition to malignant pleuritis. This subgroup had a median survival of 25.5 months. Of all 30 patients, there have been 2 postoperative mortalities from pneumonia, and 21 of 25 are deceased from cancer. Four patients are alive with no evidence of disease at 18, 26, 49, and 74 months. The pattern of recurrences included 6 of 30 patients with isolated local recurrence (primarily patients who did not undergo pneumonectomy), 3 of 30 with local and distant recurrence, and 12 of 30 with local control and distant recurrence (i.e., bone, brain, spine, liver, and contralateral lung).

Our findings are consistent with those of another group that has investigated the combination of surgery and intraoperative treatment directed at residual microscopic disease for NSCLC with malignant pleuritis.³⁰ This group randomized 22 patients to either surgery and systemic chemotherapy or surgery and systemic chemotherapy plus intraoperative hyperthermic cisplatin lavage. There were 11 patients in each group. The median survival for the group receiving intraoperative chemotherapy lavage was 20 months versus 6 months for the group receiving surgery and systemic treatment but no intraoperative adjuvant for the pleura. Interestingly, most of the patients had N₀ disease, but survival values were similar to those in our study, in which almost all patients had N₂ disease. Whether this finding is a function of the treatments or lack of significance of nodal status in the setting of malignant pleuritis is unclear. Regardless, the findings corroborate our hypothesis that the malignant pleuritis component of this disease warrants a local treatment and that there is no role for surgery, with or without systemic treatment, without a separate modality directed at the malignant pleuritis. We have been sufficiently encouraged by these findings to continue with our work.

SUMMARY

The role, if any, for PDT in the treatment of mesothelioma is not yet established. The number of centers exploring this technology is limited because it is labor-intensive and requires not only specialized equipment but also physicist support. The number of patients treated in the various trials is small, and no definitive conclusions can be drawn. Further complicating the interpretation of published results is the number of variables (e.g., type of sensitizer, light dose, drug dose, drug-light interval, methods of light measurement, technique of light delivery, and surgical debulking techniques) that differ between studies. In addition, most of the reports are phase I and II studies. The final outcome of these studies, with respect to survival, is of limited value. The only phase III study, which was performed with an earlier-generation photosensitizer and accepted gross disease after debulking, reported no advantage for the use of PDT in combination with surgery and immunochemotherapy. To date, the most that can be said about this treatment approach is that intraoperative PDT can be performed safely in experienced centers and that there are some encouraging results, especially in patients with stage I and II MPM, particularly with the newer-generation photosensitizers. The treatment has the important advantage of permitting lung-sparing procedures.

EDITOR'S COMMENT

Photodynamic therapy is another innovative technique that attempts to address the issue of R₁ cytoreduction resulting in local recurrence. This is an excellent example of an innovative therapy that can be developed and perfected in a relatively high volume center.

–LZ

REFERENCES