Small-Cell Lung Cancer, Mesothelioma, and Thymoma

SMALL-CELL LUNG CANCER

Staging and prognosis

The TNM staging system, used for all NSCLC patients, does not predict well for survival in SCLC patients and is generally not utilized in SCLC, except for surgical staging (see chapter 6, Table 1). Rather, SCLC is usually described as either limited (M0) or extensive (M1), although these general terms are inadequate when evaluating the role of surgery. Patients with SCLC who have stages I–III disease, excluding those with a malignant pleural effusion, are classified as having limited disease. These patients constitute approximately one-third of all SCLC patients. The remaining SCLC patients fall into the extensive-disease category, which includes any patient with a malignant pleural effusion or any site of distant disease, such as the brain, liver, adrenal gland, bone, and bone marrow.

The staging of lung cancer must be conducted in a methodical and detailed manner to permit appropriate therapeutic recommendations and to allow comparison of treatment results from different institutions.

Stage is commonly reported as either clinical or pathologic. The former is based on noninvasive (or minimally invasive) tests, whereas the latter is based on tissue obtained during surgery (see chapter 6).

The most important prognostic factor in lung cancer is the stage of disease. Within a given disease stage, the next most important prognostic factors are performance status and recent weight loss. The two scales used to define performance status are the Eastern Cooperative Oncology Group (ECOG) performance status system and the Karnofsky performance index (see Appendix 1). In short, patients who are ambulatory have a significantly longer survival. Those who have lost ≥ 5% of body weight during the preceding 3–6 months have a worse prognosis.

Pathology and pathophysiology

SCLC tends to present with a large central lung mass and associated extensive hilar and mediastinal lymphadenopathy. Clinically evident distant metastases are present in approximately two-thirds of patients at diagnosis. Additionally, data from autopsy examination indicate micrometastatic disease in 63% of patients who died within 30 days of attempted curative resection of SCLC. Thus, it is a systemic disease at presentation in the majority of patients.

SCLC is a small, blue, round cell tumor that is primitive and undifferentiated at the light microscopic level. Electron microscopy demonstrates its neuroendocrine derivation by the presence of dense core granules. The immuno­histochemical evidence of neuroendocrine derivation includes positive staining for chromogranin, synaptophysin, and other proteins. The APUD (amine precursor uptake and decarboxylation) machinery present in the dense core granule leads to the production of biologically active amines and promotes the synthesis of polypeptide hormones such as ADH and ACTH. Para­neoplastic syndromes due to hormone excess result. The most common of these syndromes, syndrome of inappropriate antidiuretic hormone secretion (SIADH), occurs in approximately 10% of patients with SCLC. Hypercortisolism and a Cushing’s-like syndrome are more rare, seen in only 1%–2% of patients.

Treatment

TREATMENT OF DISEASE LIMITED TO LUNG PARENCHYMA

Surgery

The majority of patients with SCLC present with advanced-stage disease. In the 5%–10% of patients whose tumor is limited to the lung parenchyma, very often the diagnosis is established only after the lung mass has been removed. If, however, the histology has been determined by bronchoscopic biopsy or fine-needle aspiration and there is no evidence of metastatic disease following extensive scanning, examination of the bone marrow, and biopsy of the mediastinal lymph nodes, resection should be performed. Adjuvant chemotherapy is recommended because of the high likelihood of the development of distant metastases following surgery.

The surgical approach in SCLC is similar to that used in NSCLC: A lobectomy or pneumonectomy should be followed by a thorough mediastinal lymph node dissection. Tumor resection in SCLC should be limited to ­patients who have no evidence of mediastinal or supraclavicular lymph node ­metastases. Recent data suggest that patients with SCLC, presenting as a solitary pulmonary nodule and proven pathologically to be stage I, have a 5-year survival rate of ~70% when treated with resection and adjuvant ­chemotherapy.

TREATMENT OF DISEASE LIMITED TO THE THORAX

Approximately one-third of SCLC patients present with disease that is limited to the thorax and can be encompassed within a tolerable radiation portal. In early studies in which either radiation therapy or surgery alone was used to treat such patients, median survival was only 3–4 months, and the 5-year survival rate was in the range of 1%–2%. The reason for the failure of these therapies was both rapid recurrence of intrathoracic tumor and development of distant metastasis.

Chemotherapy

During the 1970s, it became apparent that SCLC was relatively sensitive to chemotherapy. Various combination chemotherapy regimens were used to treat limited SCLC. Although none of the regimens was clearly superior, median survival was approximately 12 months, and the 2-year survival rate was approximately 10%–15%. It appears that maintenance chemotherapy adds little to survival in patients with limited SCLC.

Chemotherapy plus thoracic irradiation

One of the major advances in treating SCLC in the past 15 years is the recognition of the value of early and concurrent thoracic chemoradiation therapy. This advance was clearly facilitated by the increase in therapeutic index when PE (cisplatin [Platinol]/etoposide) chemotherapy is given with thoracic irradiation, as opposed to older anthracycline or alkylator-based regimens. Although the major impact from this approach is improved locoregional control, there are also hints from randomized trials that early control of disease in the chest can also reduce the risk of distant metastasis.

An intergroup trial directly compared once-daily with twice-daily fractionation (45 Gy/25 fractions/5 weeks vs 45 Gy/30 fractions/3 weeks) given at the beginning of concurrent chemoradiation therapy with PE. Initial analysis showed excellent overall results, with median survival for all patients of 20 months and a 40% survival rate to 2 years. With a minimum follow-up of 5 years, survival was significantly better in the twice-daily than in the once-daily irradiation group (26% vs 16%). The only difference in toxicity was a temporary increase in grade 3 esophagitis in patients receiving twice-daily radiation therapy.

Outcomes for patients with limited-stage SCLC have improved significantly over the past 20 years. In an analysis of phase III trials during this period, median survival was 12 months in the control arm in 26 phase III studies initiated between 1972 and 1981, compared with 17 months in studies between 1982 and 1992 (P < .001). Five studies demonstrated a statistically significant improvement in survival in the experimental arm compared with the control arm. Interestingly, all five studies involved some aspect of thoracic radiation therapy (three trials compared chemotherapy alone vs chemoradiation therapy; one compared early with late radiation therapy; and one compared daily vs twice-daily thoracic radiation therapy). Similarly, data from the Surveillance, Epidemiology, and End Results (SEER) database demonstrate that the 5-year survival rate has more than doubled from 1973 to 1996 (5.2% vs 12.2%, .0001).

Current recommendations Although important questions remain as to the optimal radiation doses, volumes, and timing with regard to chemotherapy, a reasonable standard is to deliver thoracic irradiation concurrently with PE chemotherapy (cisplatin [60 mg/m² IV on day 1] and etoposide [120 mg/ m² IV on days 1–3]). An attempt is made to integrate thoracic irradiation as early as possible, during cycle 1 (or 2). Fried et al performed a meta-analysis evaluating early vs late timing of radiation therapy in limited-stage SCLC. Earlier radiation therapy was defined as prior to 9 weeks after initiation of chemotherapy vs late radiation therapy (≥ 9 weeks). Seven trials (n = 1,542 patients) were included in the analysis. They reported a small but significant improvement in 2-year overall survival for early vs late radiation therapy (5.2%, .03). This finding is similar to the benefit of adding radiation therapy or prophylactic cranial irradiation to chemotherapy. A greater difference was evident for the subset of patients receiving early rather than late hyperfractionated radiation therapy and platinum-based chemotherapy. Hyperfractionated accelerated fractionation should be considered, given the results of the intergroup 0096 trial. The data extant do not indicate that chemotherapy beyond 4 cycles has a favorable impact on long-term outcome.

Irradiation can be incorporated sequentially with chemotherapy; however, this approach appears to be inferior to early concurrent therapy and should be reserved for use in those for whom concurrent approaches are predicted to be excessively toxic. Takada et al reported on a randomized trial of concurrent vs sequential thoracic radiotherapy in combination with PE (Platinol/etoposide) in over 200 patients with limited-stage SCLC demonstrated a benefit to concurrent therapy, with a median survival of 27.0 months (30%; concurrent arm) vs 19.7 months (20%; sequential arm, .097). Thoracic radiation therapy consisted of 45 Gy over 3 weeks, starting either with the first cycle of PE in the concurrent arm or after the fourth cycle in the sequential arm.

Results of an intergroup trial indicate that radiation therapy strategies that increase biologic dose can improve local control and survival. Further exploration of accelerated fractionation or conventional doses > 45 Gy is warranted and is currently being investigated in prospective trials.

Komaki et al recently reported on a phase I dose-escalation trial of thoracic radiotherapy with concurrent chemotherapy (Radiation Therapy Oncology Group [RTOG] 9712). In this regimen, the initial (larger) radiation field was treated once a day, and the smaller boost field was treated twice daily, to a maximum tolerated dose of 61.2 Gy.

Movsas et al reported the results of the first Patterns of Care Study (PCS) for lung cancer in the United States. This study was conducted to determine the national patterns of radiotherapy practice in patients treated for nonmetastatic lung cancer in 1998–1999. As supported by clinical ­trials, patients with limited-stage SCLC received chemotherapy plus radiotherapy more often than radiotherapy alone (92% vs 5%, P < .0001). However, the median radiotherapy dose was 50 Gy, 80% at 1.8–2.0 Gy per fraction. Only 6% of patients received hyperfractionated (twice-daily) radiotherapy. A total of 22% received prophylactic cranial irradiation (PCI), with a median dose of 30 Gy in 15 fractions. As key studies supporting twice-daily radiotherapy in PCI and NSCLC were published in 1999, the penetration of these trials will be assessed in the next PCS lung survey.

Interestingly, Choi et al reported long-term survival data from their phase I trial assessing chemotherapy with either standard daily radiotherapy or accelerated twice-daily radiotherapy as from the Cancer and Leukemia Group B (CALGB) 8837 trial. They previously reported that the maximum tolerated dose was 45 Gy in 30 fractions for twice-daily radiotherapy and > 70 Gy in 35 fractions for once-daily radiotherapy. The 5-year survival estimated (from this phase I trial) for the twice-daily arm was 20%, vs 36% for the once-daily radiotherapy arm. They suggest a phase III randomized trial to compare standard daily radiotherapy (to 70 Gy) vs twice-daily radiotherapy (to 45 Gy). Indeed, the long-term results of a phase III trial comparing once-daily irradiation (to 50.4 Gy in 28 fractions) vs twice-daily irradiation (to 48 Gy in 32 fractions via a split course) demonstrated similar outcomes in either arm. The median and 5-year survival rates of patients in this study (21 months and 20%, respectively) were similar to those reported by Turrisi et al.