The overriding clinical question in the management of lung cancer is whether or not a pulmonary resection should be done. This continues to be true despite the

increasing sophistication and complexity of radiation therapy and systemic therapies that have developed over the past 30 years, and despite the fact that lung cancer is a systemic disease in the great majority of cases. The reasons for the importance of surgery are that it is curative in low-stage situations (localized disease), and systemic treatments are marginally effective at best. In addition,

pulmonary resection provides a relatively accurate prognosis by pathologic staging of the primary tumor and the regional lymph nodes.

The decision about surgical treatment of lung cancer depends on the clinical stage

and the histology. This chapter will address the surgical decision as it pertains to small cell lung cancer from a historical perspective.

Clinical Biology of Small Cell Lung Cancer

Small cell lung cancer established itself as an entity distinct from other types of lung cancer, based on several clinical observations made in the 1960s. The prognosis after surgical treatment was dismal, as demonstrated by the British Medical Research Council randomized trial of surgery versus radiation therapy. This study showed a 5-year survival rate of 1% and no cures by surgery, only a

50% Resection rate in patients randomized to surgery, and a better (though still poor) outcome for the patients assigned to the radiation therapy arm.

An autopsy study done at the U.S. National Cancer Institute demonstrated

the reason for the poor outcome after local treatment of small cell lung cancer. In patients dying within 30 days of apparent complete resection, 70% had demonstrable metastases and regional persistence of small cell cancer at postmortem examination. The VA Lung Group found that the survival of small cell lung cancer patients could be prolonged by chemotherapy in a prospective randomized placebo control study.(4) This was not true for the other lung cancer cell types. Finally, analysis of the data base, upon which the original American Joint Commission on Cancer Staging TNM staging system was based, showed a 2-year survival rate of 5% for small cell lung cancer patients regardless of stage.(5)

As a consequence of these types of observations, small cell lung cancer was considered a nonsurgical disease. It was regarded to be metastatic by definition and was placed within the purview of the medical oncologist by virtue of its responsiveness to chemotherapy.(6)

Chemotherapy and Radiation Therapy

During the late 1970s and early 1980s, the effectiveness of chemotherapy increased when new agents such as Adriamycin, cisplatin, and etoposide became available and were incorporated into combination regimens. The strategies of adjuvant chemotherapy and multimodality therapy were developed and found to be useful for treatment of some types of cancers in certain clinical situations.

Since small cell cancer is responsive to chemotherapy, it became the object of aggressive treatment programs. Response rates rose to the 60 to 70% range, including complete remissions, especially in limited stage disease (confined to the lung of origin and mediastinum). Sites of relapse became an issue, and the role of chest irradiation was established to try to minimize “recurrence” (actually persistence) at the primary site. (7) However, there is local recurrence (treatment failure) at the primary site in about one-third of cases despite the combining of chest irradiation with chemotherapy. Over the past 15 years or so, little progress has been made in improving the chemotherapy for small cell lung cancer so that the median survival for limited-stage patients remains slightly over 1 year and the search for additional effective systemic agents continues. (8,9)

Surgery Reconsidered

As experience with chemotherapy began to accrue, consideration of surgical treatment for small cell lung cancer resurfaced, this time as an adjuvant to induction chemotherapy.(10)

Being a local treatment, surgical removal of the primary site and regional lymph nodes would be able to control the residual disease in the chest once the metastatic problem was controlled by systemic therapy. An advantage of this approach was believed to be the ability to avoid the combination of chemotherapy (especially, doxorubicin-based regimens) and thoracic irradiation, since such a combination was fraught with considerable mediastinal and pulmonary toxicity. During the 1980s, a small number of phase II uncontrolled experiences were published in which selected groups of patients were submitted for pulmonary resection after chemotherapy.(10-15) Table 10–1 summarizes these experiences. These were heterogeneous groups of patients with a variety of preoperative chemotherapy exposures selected from various populations of small cell lung cancer patients. Despite the heterogeneity, some of the clinical observations were similar. Removal of the tumor often required pneumonectomy. Resectability rates were high but lower than one would expect in a non–small cell population of similar clinical stages. The pathologic complete response rate to chemotherapy was in the teens, and residual non–small cell histologies were discovered in an appreciable portion of patients. Local recurrence rates, when specified, were low. A common feature of all of these experiences was that the prerequisite to pulmonary resection was favorable response (tumor shrinkage) to preoperative chemotherapy.

For the sake of comparison, Table 10–2 lists four large surgical series of lung cancer patients predating the chemotherapy era.(16-19) These four series comprise 3150, 3660, 1820, and 1800 patients, respectively, and report outcomes for a total of 448 resected small cell lung cancer patients (4.3% of the total number of lung cancers). This table seems to indicate that there is a population of patients with small cell lung cancer that has low-stage disease and does well even without chemotherapy. Expanding upon this type of observation, another combined modality strategy has been to use surgery as initial treatment for patients with low clinical stage (i.e., stage I), and deliver systemic therapy as a postoperative adjuvant. This strategy became more tenable as imaging technology improved and allowed for more sensitive preoperative staging to be accomplished. Table 10–3 summarizes a number of such reports. 15,20–24

In this series of observations, the outcomes were good, except for the first citation on the table. The majority of these patients were in stage I at the time of initial treatment and are thereby in a select group, since small cell lung cancer usually arises in large central airways and mediastinal node metastases are usually present.

Reference to Table 10–2 illustrates this point when one considers that the denominator for the 448 patients in the first three series totaled over 10,400 patients.