114: Overview and Historical Context of Malignant Pleural Diseases

Most malignant diseases of the pleura present with a unilateral pleural effusion or thickening. Malignant diseases include the very common secondary malignancy metastatic to the pleura, the less common lung cancer patient with pleural carcinomatosis, and the uncommon patient with primary malignant pleural mesothelioma (MPM). The low morbidity and accuracy of diagnostic thoracoscopy and pleural biopsy have dramatically increased our understanding and treatment of these diseases. This section of chapters provides important details and management of this group of primary malignant and secondary malignant diseases of the pleura.

Ironically, much of our insight has been gained by trying to understand the least common yet deadliest of this group of diseases: pleural mesothelioma. The current incidence of pleural mesothelioma within the United States is 2000 to 3000 cases per year as compared with esophageal and lung cancer, which are at least four and 50 times more common, respectively.¹ Few physicians will treat more than a handful of cases of MPM over the course of their professional careers. Even fewer academic centers in North America and Europe have been able to acquire a collective experience large enough to develop new treatment protocols for this devastating disease. The Brigham and Women's Hospital (BWH) and Dana-Farber Cancer Institute (DFCI) in Boston, Massachusetts, have gained a large experience treating MPM over the last 25 years.

The recognition of mesothelioma as a cancer and the development of treatment options are recent developments in the context of medical history. In 1950, Stout described malignant mesothelioma as a separate pathologic entity.² Stout also described the three histologic subsets: epithelial, fibrosarcomatous, and mixed.

In 1960, Wagner et al.³ published the first mesothelioma case series, reporting on 33 patients from a South African asbestos mining town with known occupational and environmental crocidolite exposure. In the 1970s, a landmark study by Selikoff⁴ was published which established a firm link between asbestos exposure and mesothelioma. The investigators followed 17,800 asbestos insulation workers in the United States and Canada for a period of up to 50 years. They found that the incidence of mesothelioma within this group increased rapidly starting 20 to 25 years after the first exposure. Peak incidence occurred at 40 to 45 years after exposure. Seven percent of all deaths in this group of asbestos workers were due to mesothelioma, a shockingly high incidence for a rare cancer. Family members of asbestos workers also have a substantial increased risk, termed “bystander risk,” thought to be secondary to exposure to hair and clothes brought into the home.⁵

Early efforts at surgical and nonsurgical treatments were disappointing. Worn⁶ published one of the first series of patients undergoing extrapleural pneumonectomy (EPP) in 1974 reporting a 5-year survival rate of 10% and a median survival of 19 months. Butchart et al.⁷ published their initial experience with EPP for maximal surgical debulking of pleural mesothelioma in 1976. EPP had previously been used for tuberculous empyema, but was an operative technique that had always been associated with a high perioperative mortality. In Butchart's series, EPP for MPM had a perioperative mortality rate of 31%, a 5-year survival of 3.5%, and a median survival of 10 months. Although operative mortality has now been reduced to less than 4%, EPP is a technically demanding operation, and details of the operative technique are included in Chapters 122 and 123.

Initial studies investigating adjuvant chemotherapy and radiation therapy repeatedly showed little to no activity against the disease. Median survival of patients enrolled in therapeutic trials varied from 3 to 17 months with the majority falling in the 6 to 10 month range.^8,9 As the genetic and biochemical abnormalities of the malignant mesothelioma cell became understood, the chemotherapeutic options have dramatically improved.

New England has had a rich maritime military history. In August 1776, patriot soldiers from Marblehead and Salem, Massachusetts, rowed George Washington's army to safety across Long Island Sound after the defeat on Brooklyn Heights. Three of the first six frigates built for the fledgling United States Navy were built in New England or New York. The large whaling and cod fishing fleets from New Bedford, Nantucket, and Gloucester were the major oil producers for over 200 years.

The pace of production of United States naval ships during World War II reached one ship per week in the large shipyards of New England and New York. Asbestos slurry was sprayed upon the bulkheads of the ships to insulate the compartments from the cold of the North Sea, as well as insulation against fire within individual sections of the ship. Although quickly and easily applied to the bulkheads, this asbestos slurry would flake and particles of asbestos dust would be suspended in the air once it had dried. Unaware of the long-term complications of this exposure, the shipyard workers did not wear protective clothing or masks. Many mesothelioma patients who served on these ships describe a cloud of white dust below decks whenever the large guns of the warship were fired.

A large proportion of the New England population came into contact with substantial quantities of asbestos by either working within the New England shipyards, or serving in the navy. Asbestos was also commonly used to insulate heaters within the home, exposing an even larger New England population.

The long latency period from exposure to development of the cancer has contributed to the high frequency of pleural mesothelioma in the greater Boston area during the past two decades. Prospective studies following people with known asbestos exposure have demonstrated a rapid rise in the incidence of malignant mesothelioma beginning at 20 years post exposure and a peak incidence of approximately 0.6% per year 40 to 45 years after exposure.

Asbestos continued to be used in manufacturing for many years. In the United States, it wasn't until 1986 that the Toxic Substance Control Act addressed the health risks of asbestos giving the EPA broad authority to regulate the manufacture, use, distribution in commerce, and disposal of the carcinogenic substance.

When one considers the timing of these federal regulations, the latency of the disease, the geographical distribution of asbestos exposure, and the history of asbestos use, it is no coincidence that the BWH has become an epicenter of treatment for MPM.

The Sydney Farber Cancer Institute was founded in 1949, and originally served only childhood cancers. In 1969, it expanded its mission to treat adult malignancies, and received federal designation as a regional Comprehensive Cancer Center in 1973. It was renamed the Dana-Farber Cancer Institute in 1983. Located in Boston, Massachusetts, across the street from both the Peter Bent Brigham Hospital (which became the Brigham and Women's Hospital in 1980), and the Harvard Medical School, it soon became a major referral center for both aggressive and unusual malignancies within the New England area. Mesothelioma was among these cancers.

In March of 1980, Antman, et al.¹⁰ published in the American Journal of Medicine the experience with the first 40 patients treated at the Sydney Farber Cancer Institute with malignant mesothelioma. These patients had been treated between 1965 and 1978. Thirty-four of the patients had the pleural form of the disease while six patients had peritoneal mesothelioma. Sixty-three percent of these patients reported either an asbestos exposure or were employed in New England shipyards, generally during World War II. In this series, adriamycin-containing chemotherapy regimens induced a partial remission in 40% of the previously untreated patients. Yet, despite these remissions, the majority of patients (78%) ultimately died of local disease. Subtotal resection in this series, and others,¹¹ resulted in prolonged survival. Specifically, the 10 patients in Antman's review who underwent subtotal resections had a median survival of 15 months, compared to 8.5 months for the 20 patients who underwent only diagnostic operations and other treatments. Further analysis revealed that the median survival was a mere 4.2 months for patients who were diagnosed with limited disease but chose only supportive care. The authors advocated a multimodality approach incorporating maximal surgical resection with adjuvant chemotherapy and radiation therapy.

In 1984 Karen Antman organized a prospective multimodality protocol for MPM at the DFCI. This ambitious protocol started with an EPP, as had been previously described by both Worn and Butchart. Chemotherapy consisted of cyclophosphamide at a dose of 600 mg/m², combined with adriamycin 60 mg/m², to a cumulative dose of 450 mg/m². After 1985, patients also received cisplatinum at 75 mg/m² (CAP chemotherapy). Radiation directed at previous sites of bulky disease was given to a dose of 5500 rads after the chemotherapy.

The accurate pathologic diagnosis of malignant mesothelioma versus a primary adenocarcinoma of the lung or a secondary malignancy metastatic to the pleura has been a barrier to treatment development. Stimulated by the need to distinguish between these histologically similar tumors, the Pathology Department at BWH drew on the large source of explanted tumors at our institution to develop a panel of immunohistochemical tests. This work is nicely summarized by two pioneers in this area in Chapter 115: Pathology of Mesothelioma.

The Division of Thoracic Surgery at the BWH was established in 1988. This separate academic division was to be dedicated to the care of patients with noncardiac thoracic diseases. The work of this surgical division began with Dr. David Sugarbaker's return to Boston from his Toronto General thoracic surgical training. The subsequent congregation of surgeons within a single institution sped the process of technical and clinical modifications, which reduced the expected operative mortality in a short period of time. An early forthright discussion of the operative technique, as well as some of the technical difficulties with the operation, appeared in the 1992 publication by Sugarbaker et al.¹²

The promising results of the BWH program reflected not only the refinement of surgical skill and improvement in perioperative care, but also identification of prognostic variables with a consequent improvement in patient selection.

In 1993, Sugarbaker et al.¹³ updated their experience after 52 patients had been treated with EPP in a trimodality setting. This analysis demonstrated significantly longer survival in patients with epithelial histology and node negative disease.

Based on these findings, a Brigham pathologic staging system was proposed.

The original Brigham staging system had four stages. Stage I was comprised of tumors confined within the pleural envelope and without lymph node involvement. Stage II, which would be modified in a few years, also consisted of tumors within the pleural envelope, but with either intraparenchymal (N1) or mediastinal (N2) lymph nodes involved with tumor.¹⁴ Stage III disease was made up of locally aggressive and unresectable tumors beyond the pleural envelope that had invaded into the mediastinum or chest wall, or through the diaphragm, or involved contralateral (N3) nodes. Stage IV disease was defined by distant metastases. This system has recently been replaced with a more predictive staging system that incorporates clinical as well as pathologic parameters, as explained by Dr. William Richards in Chapter 116, The Staging of Malignant Pleural Mesothelioma.

Despite these advances in surgical technique and refinement in prognostication and patient selection, the unfortunate fact remained that nearly all patients eventually died of their disease within 10 years of the operation. Recurrences appeared to result by direct extension from the ipsilateral hemithorax. Therefore, in the second half of the 1990s, the BWH group embarked on a new approach to multimodality therapy.

The major treatment plan of the previous 10 years had started with EPP because mesothelioma was predominantly a locoregional disease, and much of the early morbidity was from local spread. Since most patients died as a result of the primary cancer invading the diaphragm, chest wall, and mediastinal organs, initial surgical debulking was chosen prior to the initiation of chemotherapy in order to reverse the aggressive natural progression of this disease.

In 1997, Baldini et al.¹⁵ published a detailed retrospective review of 49 patients who underwent EPP and some combination of adjuvant chemotherapy and/or radiotherapy with a focus on defining patterns of failure. In this series, overall median survival was 22 months and 3-year survival, 34%. Resection margins were microscopically positive in 61% of patients and lymph nodes positive in 29%. Of the 54% of patients with recurrences, 67% percent had the first recurrence within the ipsilateral hemithorax, and 50% had recurrence at some time within the abdomen.

The potential role of intracavitary chemotherapy as a method of improving local regional control had been studied previously in a variety of abdominal malignancies. The local application of chemotherapy allows high cytotoxic levels to reach residual tumor cells by diffusion without the side effects of high dose systemic chemotherapy. Intracavitary chemotherapy with or without hyperthermia had been favorably reported in the literature.

Alberts et al.¹⁶ published a prospective randomized trial in The New England Journal of Medicine in 1996. Intraperitoneal cisplatin was compared to intravenous cisplatin in patients with stage III ovarian cancer following cytoreductive surgery. Among the 654 randomized patients, the estimated median survival was significantly longer in the group receiving intraperitoneal cisplatin (49 months) than in the group receiving intravenous cisplatin (41 months).

The decision to design a phase I dose escalation trial of heated intraoperative cisplatin at the time of EPP had been supported by the BWH, the DFCI, and the leadership of all professional groups who would be involved in patient care. The obstacles to be overcome were formidable. Protocols to maximize both patient and staff safety were designed by a multidisciplinary “heated chemotherapy team” which met once a week to develop guidelines for this novel therapy. Ideas were actively sought from surgeons, anesthesiologists, pharmacists, nurses, scrub technicians, medical oncologists, and respiratory therapists to design the method of drug delivery and disposal in the operating room.

Radical pleurectomy is an attractive alternative for patients who are unsuitable for EPP. This includes patients with a decline in their functional status and elderly patients. A radical pleurectomy leaves the lung, but can remove the central portion of the diaphragm and the ipsilateral pericardium. The technique is well described by Dr. Flores in Chapter 121.

Innovative treatments also include the use of photodynamic therapy as an adjuvant treatment following EPP. Dr. Joseph Friedberg has developed this technique and provides details in Chapter 124.

The development of new chemotherapeutic agents (Chapter 117) with better response rates suggests the potential role of using these agents in a neoadjuvant manner for advanced stage disease. Dr. Walter Weder has been an articulate spokesman of this technique and provides his data in Chapter 125.

The low morbidity associated with thoracoscopic evaluation of the diseased pleural space has opened a new treatment paradigm for malignant effusions, irrespective of cause. A thoracoscope allows the breakdown of loculations and complete drainage of the effusion for palliation of symptoms, provides sufficient histologic material for a definitive diagnosis, and allows therapeutic intervention for long-lasting palliation of symptoms. This aspect of malignant pleural disease is described well in Chapters 119 and 120.

Malignant pleural disease is a common entity. Initial diagnosis is suspected with unilateral effusion or pleural thickening. Early thoracoscopy provides not only palliation of symptoms, but also allows accurate pathologic diagnosis and assists in staging. No matter the cause of the malignant effusion, several treatment options are currently available, and more are being developed by innovative research. Much remains to be done.