Small Cell Lung Cancer Treatment & Management

Small cell lung cancer (SCLC) differs from other lung cancer types because of its rapid growth and propensity for early dissemination. Management of limited-stage small cell lung cancer involves combination chemotherapy, usually with a platinum-containing regimen, and thoracic radiation therapy. If the patient achieves a complete remission, he or she would be offered prophylactic cranial irradiation. Surgery plays little, if any, role in the management of small cell lung cancer, except in a small minority of patients who present with very early stage disease confined to the lung parenchyma incidentally resected during lung surgery for a solitary mass.

Patients with limited stage disease with apparent clinical stage T1/T2, N0 should undergo mediastinoscopy. Should the mediastinoscopy prove to be negative, these individuals might undergo surgical resection to involve lobectomy, wedge resection, or pneumonectomy together with mediastinal lymph node removal.^[4]

Brain metastasis and spinal cord compression

Management of brain metastasis includes high doses of corticosteroids (eg, intravenous [IV] dexamethasone 10 mg initially, followed by IV or oral [PO] dose of 4-6 mg q6h) and immediate radiation therapy.

Patients in whom spinal cord compression is suspected should receive a dose of IV corticosteroids even before being sent for magnetic resonance imaging (MRI). The typical dose is 10 mg of dexamethasone IV, followed by 4-6 mg IV/PO every 6 hours. Some authors prefer the IV route because of the reliability of drug delivery.

If the etiologic cause of the spinal cord compression is known (ie, a previous histologic diagnosis of SCLC), definitive management is radiation therapy and/or neurosurgical decompression, which should be started without delay. Otherwise, if the patient presents with spinal cord compression and no previous diagnosis of cancer, surgical resection, if technically feasible, provides both immediate decompression and tissue diagnosis of the cancer.

Diet, activity, and prognosis

Weight loss is an important factor indicating poor prognosis in patients with small cell lung cancer. A dietary consultation should be obtained for patients with persistent weight loss.

Performance status is another important prognostic factor. Patients who are ambulating less than 50% of waking hours have a worse prognosis; therefore, activity should be encouraged.

Small cell lung cancers may respond very quickly to chemotherapy, which carries a risk of rapid tumor lysis, especially in extensive-stage disease, with associated life-threatening electrolyte abnormalities and risk of renal shutdown. Therefore, treating physicians must remember this potential adverse effect, and patients should be hydrated adequately and, preferably, premedicated with allopurinol.

A number of platinum-based and non platinum-based chemotherapy regimens have been used in the treatment of small cell lung cancer with varying results. A recent review by Amarasena et al analyzed the data from trials to compare the effectiveness of these regimens. The investigators concluded that platinum-based chemotherapy regimens did not provide a statistically significant benefit over non platinum-based agents in survival or overall tumor response, but these agents did increase complete response rates, with an associated higher incidence of nausea, vomiting, anemia, and thrombocytopenia.^[27] Amarasena et al suggested the nonplatinum chemotherapy regimens may have a better risk-benefit profile.^[27]

Extensive-stage small cell lung cancer remains incurable with current management options, and patients are treated with combination chemotherapy. Several chemotherapy combinations are active in small cell lung cancer, but usually a platinum-containing regimen is chosen. It should be noted, however, that despite great enthusiasm over 2 decades ago, little change in survival has been shown for both limited- and extensive-stage small cell lung cancer.^{[28, 29]}

Very few new agents with activity in small cell lung cancer have been identified, and although identification of molecular targets and targeted therapies has proceeded at a brisk pace in non-small-cell lung cancer, the same has not been true for small cell lung cancer. Treatment strategies involving angiogenesis blocking agents are currently being tested.

Common combinations include cisplatin/etoposide, cisplatin/irinotecan, carboplatin/etoposide, and carboplatin/irinotecan.

A study by Schmittel et al found that carboplatin/irinotecan was not superior to carboplatin/etoposide.^[30]

For relapse, a clinical trial should be offered as an option (eg, topotecan, gemcitabine, paclitaxel, docetaxel, vinorelbine).

The table below provides some common chemotherapy regimens used in the treatment of small cell lung cancer.

Table 3. Commonly Used Chemotherapy Regimens in Small Cell Lung Cancer (Open Table in a new window)

Several chemotherapeutic agents have been identified in the last 3 decades that yield response rates in excess of 30% in previously untreated patients who have small cell lung cancer. Although cisplatin is currently the most widely used agent in combination chemotherapy programs, response rate data for single-agent cisplatin in previously untreated patients with small cell lung cancer are lacking. In previously treated patients, however, cisplatin has shown a response rate of 17%.

Currently, cisplatin, etoposide, vincristine, doxorubicin, and cyclophosphamide are the agents most commonly used to treat previously untreated patients with small cell lung cancer. The scheduling of etoposide has been demonstrated to be important in achieving a higher response rate, and currently, etoposide is given over 3 days.

Protracted oral administration of etoposide has been an acceptable initial therapy in elderly patients with extensive-stage small cell lung cancer, especially in those with poor performance status, but more recent studies suggest combination chemotherapy may be better than single-agent oral etoposide in those with good performance status.

The taxanes and topotecan have emerged as active agents in previously untreated patients with small cell lung cancer. The response rates range from approximately 40% with topotecan to 50% with paclitaxel.

Although a few studies have suggested that the response rates and survival may be comparable between single-agent etoposide and more standard combination chemotherapy regimens in previously untreated patients with small cell lung cancer, combination chemotherapy is accepted widely as being associated with superior response rates and survival.^{[1, 2, 3, 31]} A number of randomized trials have tried to answer the questions of superiority of combination over single-agent chemotherapy, the number of drugs in combination, and dose intensity, and nonrandomized trials of combination chemotherapy have shown superior response rates and survival compared with single-agent chemotherapy.

The combination of cisplatin and etoposide (PE) is currently the most widely used regimen in both limited- and extensive-stage small cell lung cancer. The combination of cyclophosphamide, doxorubicin (Adriamycin), and vincristine (CAV) has been compared with PE in at least 2 randomized trials of previously untreated extensive-stage small cell lung cancer showing similar survival outcomes. The PE combination is associated with less myelosuppression, whereas CAV has the convenience of administration in a single day (PE requires a 3-d program).

In a small study phase II trial with 100 patients found that adding bevacizumab to cisplatin/etoposide did not improve progression-free survival.^[32]

Several trials have tested the use of higher doses of standard chemotherapeutic regimens in previously untreated small cell lung cancer. Despite early enthusiasm brought on by higher initial response rates, most of these trials have failed to improve survival.^[33]

A trial by Arriagada et al comparing standard and higher doses of cyclophosphamide and cisplatin in the first cycle of chemotherapy only yielded a superior survival rate in patients receiving higher-dose chemotherapy.^[21] Higher-dose regimens, however, may cause life-threatening myelosuppression and, in the absence of survival advantage, should not be used outside of a clinical trial.

Another approach to increase the intensity of chemotherapy is to shorten the interval between cycles (increased dose density). Again, although phase II trials suggested the superiority of such an approach, randomized trials failed to show an advantage of intensive weekly chemotherapy over standard regimens. One of the problems has been myelosuppression with weekly programs, such that the planned dose intensity has not been reached. Growth factor support may overcome this, but until randomized trials are reported to show clear superiority of such an approach, it remains investigational.

High-dose chemotherapy with bone marrow or stem cell transplantation

The available data do not support the use of high-dose chemotherapy with bone marrow or stem cell transplantation because this approach has not yielded better survival rates than standard management, and it is associated with greater immediate and delayed toxicity.

Staging should be adequate before making the diagnosis of limited-stage small cell lung cancer (SCLC). Any pleural effusion should be tested cytologically for malignant cells, and isolated liver or adrenal lesions should be sampled by fine-needle aspiration before a diagnosis of limited-stage disease is made. Some authorities suggest a bone marrow examination in the absence of any other evidence of spread. (See Workup.)

Standard management involves combination chemotherapy with a cisplatin-containing regimen and concurrent thoracic radiotherapy. The chemotherapy cycles are repeated every 3 weeks; currently, no data support continuation of chemotherapy beyond 6 cycles. In North America, the chemotherapy regimen used is etoposide and cisplatin (PE). (Should the patient relapse after 6 mo of completion of induction therapy, an attempt may be made to repeat the induction regimen. Relapses before the 6-mo point would require salvage therapy.)

The ACCP guidelines recommend that patients with limited-stage disease be treated with concurrent chemoradiotherapy. Patients who experience a complete remission or have had a resection should be offered prophylactic cranial radiation. Patients with extensive-stage disease should receive 4 to no more than 6 cycles of cisplatin or carboplatin-based combination therapy. Cisplatin could be combined with etoposide or irinotecan. Patients who respond to chemotherapy can then be offered thoracic radiotherapy. Patients who relapse should be offered additional chemotherapy.^[23] The NCCN 2011 guidelines support these recommendations.^[22]

Radiotherapy

Patients are started on thoracic radiotherapy, which should begin as early as possible according to some authorities. Others advocate giving the radiation therapy concomitantly with the fourth cycle of chemotherapy.

A randomized trial reported by Takada and colleagues that compared PE with concurrent versus sequential thoracic radiotherapy reported superior 2- and 5-year survival rates (2-y survival, 35.1% vs 54.4%; 5-y survival, 18.3% vs 23.7% in favor of concurrent chemotherapy and radiation) with concurrent approach.^[34] However, hematologic toxicity was greater in the concurrent arm.

In another randomized trial, Turrisi and colleagues demonstrated a slight superiority of concurrent hyperfractionated radiotherapy given with 4 cycles of PE in limited-stage small cell lung cancer.^[35] Five-year survival rates in this trial were 26% versus 16%, in favor of hyperfractionated radiotherapy.

Prophylactic cranial irradiation

The use of prophylactic cranial irradiation (PCI) was initially considered controversial.^[36] Several randomized trials showed a decrease in central nervous system (CNS) relapse rate with PCI but no survival advantage. Additionally, patients receiving PCI had a higher incidence of neuropsychiatric dysfunction than those who did not receive PCI.^[36] The 2011 NCCN guidelines support these findings.^[22]

Arriagada et al performed a meta-analysis of randomized trials of PCI in limited-stage small cell lung cancer and showed a 5% overall survival advantage in those receiving PCI.^[21] Although such an analysis has inherent limitations, PCI is currently offered to patients with limited-stage small cell lung cancer who have achieved complete remission after having completed the full chemoradiotherapy regimen. Such therapy decreases the incidence of later intracranial metastases and prolongs survival. It should be regarded as standard therapy.

Patients with extensive-stage small cell lung cancer (SCLC) are treated with combination chemotherapy alone. Although cisplatin/etoposide (PE) remains most widely used, a randomized trial compared the combination of cisplatin with either etoposide or irinotecan in extensive-stage disease.^[37] The combination of cisplatin and irinotecan was found superior to that of PE, with a median survival of 12.8 months with the cisplatin/irinotecan combination versus 9.4 months with PE.^[37] The 2-year survival rate was also superior at 19.5% versus 5.2%.

However, a confirmatory study in the United States failed to show superiority of either regimen.^[38] Possible reasons for these results may be different dose and schedule of chemotherapeutic agents as well as genetic changes within different study populations. Although PE and irinotecan/cisplatin had comparable overall response rates and survival outcomes, the combination irinotecan/cisplatin had more gastrointestinal toxicity.^[39]

PE remains the standard of care in North America for extensive small cell lung cancer. A German clinical trial reported that topotecan/cisplatin had a similar overall response rate to PE in extensive small cell lung cancer but a better time to progression and objective response rate than did PE.^[40] A trial comparing the 2 regimens in North America has not yet been performed.

Radiotherapy

Radiotherapy is used only to palliate symptoms, if required (eg, for painful bone metastases) in extensive-stage small cell lung cancer. Response rates are excellent, but patients invariably relapse.

Prophylactic cranial irradiation

As with limited-stage disease, prophylactic cranial irradiation (PCI) should be offered to all responding patients with extensive stage small cell lung cancer, and this treatment should be considered standard therapy for this stage of the disease in these patients. Brain metastases at the time of initial diagnosis in extensive small cell lung cancer are present in about 18% of patients and increase to about 80% at 2 years.

A study by the European Organization for Research and Treatment of Cancer (EORTC) randomized patients responding to systemic chemotherapy between PCI versus no PCI and found 1-year survival for the PCI-treated group was 27.1% compared with 13.3% for those who did not receive PCI.^[36] PCI not only reduced the incidence of brain metastases but also improved disease-free and overall survival rates.

Gamma Knife stereotactic radiosurgery

Gamma Knife stereotactic radiosurgery is a salvage option for patients with brain metastases for whom previous whole brain irradiation has failed.^[41]

Patients with relapsed small cell lung cancer (SCLC) have an extremely poor prognosis. Those whose disease does not respond to or which progresses on initial treatment (ie, those with refractory disease) or those whose disease relapses within 6 months of completion of therapy have little chance of responding to additional chemotherapy.

In general, PE given after CAV failure produces better response rates than CAV given after PE. Topotecan received US Food and Drug Administration (FDA) approval for use in chemotherapy-sensitive disease after failure of front-line chemotherapy. Because of the lack of long-term benefit of this therapy, however, patients with relapsed or refractory small cell lung cancer should be encouraged to enroll in clinical trials, if their condition permits.

Physicians should be aware of potential complications such as spinal cord compression, tumor lysis syndrome, and electrolyte abnormalities.

Spinal cord compression

New onset of back pain in patients known to have malignant disease should raise the suspicion of cord compression. A thorough neurologic examination and radiologic evaluation of the spine is indicated with any suspicion of spinal cord compression. This is an oncologic emergency. The goal is to prevent development of neurologic deficit. Once present, a neurological deficit can progress within hours to cause complete paraplegia. Any delay in instituting appropriate therapy may result in permanent neurologic deficit.

Tumor lysis syndrome

Tumor lysis can occur rapidly in patients with small cell lung cancer (SCLC) on institution of chemotherapy, especially in extensive-stage disease. The laboratory features of tumor lysis syndrome (TLS) are hyperuricemia, hyperphosphatemia, hypocalcemia, and hyperkalemia. Patients should be well hydrated and, preferably, premedicated with allopurinol. The management of established tumor lysis syndrome is urinary alkalinization, correction of electrolyte abnormalities, and dialysis, if necessary.

Electrolyte abnormalities

Small cell lung cancer is associated with a number of electrolyte abnormalities because of frequent production of peptide hormones. The most common abnormality is hyponatremia, and, if severe, it may cause neurologic symptoms and signs, including seizures, coma, and death. Prompt recognition of this abnormality and severity is important.

Hyponatremia results from inappropriate secretion of antidiuretic hormone (ADH), which results in the inability of the kidneys to excrete free water. Syndrome of inappropriate ADH (SIADH) is reported in 5-10% of patients with small cell lung cancer. The serum sodium level is usually less than 130 mEq/L. Other causes of hyponatremia (ie, volume depletion, abnormal renal function) must be excluded. Fluid restriction and pharmacologic therapy in the form of demeclocycline (a tetracycline antibiotic that decreases the sensitivity of renal tubules to the action of ADH) are usual forms of management.

Patients in whom lung cancer is suspected may require consultation with a pulmonologist to establish a diagnosis. Once a diagnosis is established, medical and radiation oncologists should be consulted to complete the staging workup and devise a management plan.

Patients with small cell lung cancer (SCLC) require close monitoring for adverse effects and response to therapy. Blood work, including a complete blood cell (CBC) with differential, is needed before each cycle of chemotherapy to ensure marrow recovery before the next dose of chemotherapy is administered. Renal function should be monitored because of nephrotoxicity from cisplatin.

Computed tomography (CT) scans should be obtained after 2 cycles of therapy to assess response before chemotherapy is continued.

Serum lactate dehydrogenase (LDH), if elevated before start of therapy, is a good marker for response and should be monitored.

Patients who smoke cigarettes should be encouraged to quit. A meta-analysis by Parsons et al suggested that smoking cessation after diagnosis of early-stage lung cancer may improve prognosis, probably by reducing cancer progression.^[13] Evaluation of data from 9 studies showed that the estimated 5-year survival in limited-stage small cell lung cancer was 63% in patients who quit smoking versus 29% in those who continued to smoke.^[13]