Small-cell lung cancer

Jackman, David M ; Johnson, Bruce E . The Lancet 366.9494 (Oct 15-Oct 21, 2005): 1385-96. Turn on hit highlighting for speaking browsers by selecting the Enter buttonHide highlighting

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Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, proto-oncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.

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Headnote

Small-cell lung carcinoma is an aggressive form of lung cancer that is strongly associated with cigarette smoking and has a tendency for early dissemination. Increasing evidence has implicated autocrine growth loops, protooncogenes, and tumour-suppressor genes in its development. At presentation, the vast majority of patients are symptomatic, and imaging typically reveals a hilar mass. Pathology, in most cases of samples obtained by bronchoscopic biopsy, should be undertaken by pathologists with pulmonary expertise, with the provision of additional tissue for immunohistochemical stains as needed. Staging should aim to identify any evidence of distant disease, by imaging of the chest, upper abdomen, head, and bones as appropriate. Limited-stage disease should be treated with etoposide and cisplatin and concurrent early chest irradiation. All patients who achieve complete remission should be considered for treatment with prophylactic cranial irradiation, owing to the high frequency of brain metastases in this disease. Extensive-stage disease should be managed by combination chemotherapy, with a regimen such as etoposide and cisplatin administered for four to six

cycles. Thereafter, patients with progressive or recurrent disease should be treated with additional chemotherapy. For patients who survive long term, careful monitoring for development of a second primary tumour is necessary, with further investigation and treatment as appropriate.

Small-cell lung cancer is a distinct clinical and histological entity within the range of lung cancers. Its unique pathological features were first recognised in 1926 by Barnard.1 Watson and Berg2 later described the distinct clinical features of this disease in detail, noting the predominantly central location on chest radiography, the tendency for early dissemination, high initial response rates to chemotherapy, and the high frequency of metastases at autopsy.2 These observations remain accurate 40 years later: small-cell lung cancer is the most aggressive of lung-cancer subtypes. Although most patients' tumours respond to chemotherapy, more than 95% of patients eventually die from the cancer.3 Small-cell carcinoma accounts for 14% of new lung-cancer cases, or about 77 000 of the estimated 550 000 lung cancers in the USA and Europe in 2004.4,5 The vast majority, more than 95%, of these patients develop small-cell lung cancer because of tobacco smoking. The risk of developing the cancer increases both with the number of cigarettes smoked each day and with the duration of smoking.6 This risk begins to decrease with smoking cessation compared with that for individuals who continue to smoke.7

Scientific advances have been made in defining the biology of small-cell lung cancer and have increased our ability to manage this cancer clinically. This review focuses on the underlying molecular changes in the disorder, its presenting signs and symptoms, and its diagnosis, staging, and treatment.

Molecular biology

The specific sequence of genetic alterations leading to small-cell lung cancer is still unclear. However, several important genetic and molecular changes have been noted, including the identification of autocrine growth loops, proto-oncogene activation, and loss or inactivation of tumour-suppressor genes.

Autocrine growth loops

Gastrin-releasing peptide, the human homologue of the amphibian peptide bombesin, has a role in embryonic development and adult repair of bronchial epithelia.8 Small-cell-lung-cancer cell lines produce gastrin-releasing peptide and neuromedin B.9,10 Small-cell lung cancers also express receptors for these two peptides as well as bombesin receptor subtype 3.11 As many as 85% of small-cell-lung-cancer cell lines express at least one of these three receptors.12 The secretion of the peptides by the small-cell lung cancer and subsequent binding to their receptors leads to receptor activation and an autocrine-stimulated growth loop in tumour cells.13 A monoclonal antibody directed against gastrin-releasing peptide causes growth inhibition of small-cell lung cancers both in vitro and in the athymic nude mouse model.13 A patient treated with this monoclonal antibody had a complete response.14 There are no current trials with the monoclonal antibody for patients with small-cell lung cancer because of lack of clinically usable antibody.

The tyrosine kinase receptor, c-kit, is mutated and activated in most gastrointestinal stromal tumours and could have a role in small-cell lung cancer also.15 The ligand stem-cell factor is expressed by and secreted from small-cell lung cancers, binds to its receptor, c-kit, and

causes receptor activation.16,17 This process stimulates the growth of the cancer cells, forming an autocrine loop. The c-kit receptor is found in up to 70% of small-cell-lung-cancer lines and tumours.16,18 Moreover, mutations have been identified in the c-kit receptor of 10% of small-cell lung cancers.19 The tyrosine kinase inhibitor of c-kit, imatinib, has been investigated in small-cell lung cancer. In-vitro and invivo models show inhibition of growth when some cell lines are treated with imatinib.20,21 However, two phase II trials of imatinib in small-cell lung cancer have shown no antitumour activity in previously treated or untreated patients.22,23 Owing to this lack of efficacy, no further phase II and III trials of imatinib for patients with small-cell lung cancer are planned.

Proto-oncogenes

The MYC oncogenes (CMYC, NMYC, and LMYC) encode nuclear phosphoproteins that directly regulate gene transcription, increase cell growth, and cause cell-cycle progression.24 The overexpression of MYC proteins in small-cell lung cancer is largely a result of gene amplification.25 Such overexpression leads to more rapid proliferation and loss of terminal differentiation. MYC overexpression occurs in 16-32% of small-cell lung cancers and in 40% of cell lines established from patients whose disease progressed after chemotherapy.26,27 Treatment of small-cell-lung-cancer cell lines with MYC antisense DNA and tretinoin caused down-regulation of CMYC expression and slowed the cell growth rate.28 Conversely, transfection of CMYC into small-cell-lung-cancer cell lines causes an increase in cell proliferation and a change in cellular morphology.29

Tumour-suppressor genes

The loss of genetic material from the short arm of chromosome 3 was documented in small-cell lung cancer more than 20 years ago. Frequent chromosomal deletions of 3p, 4p, 5q, 16q, 13q, and 17p have been found by both loss-of-heterozygosiry analysis30 and comparative genomic hybridisation." The loss of alleles from the short arm of chromosome 3 is the most common deletion of tumour DNA in small-cell lung cancer, found in more than 90% of tumours.30,32 Specific regions of homozygous deletions and loss of heterozygosity have been identified in the region of (3p[14-25]),33 which supports the hypothesis that the 3p arm carries several tumour-suppressor genes (table 1).

Four genes are of particular interest as possible tumour suppressors in small-cell lung cancer. First, the fragile histidine triad gene (FHIT) encodes the enzyme diadenosine triphosphate hydrolase,34 which is thought to have an indirect role in proapoptosis and cell-cycle control. Second, the RAS effector homologue (RASSF1), encodes a microtubule-binding protein. RASSF1 interacts with the microtubules, causing stabilisation and inducing G^sub 1^, G^sub 2^/M arrest.35 The loss of RASSF1 function allows tumour cells to grow more rapidly. The third potential tumour-suppressor gene is the retinoic acid receptor β, through which retinoids exert activity against activator protein 1(36) and induction of apoptosis.17 FUS1, a fourth potential tumour suppressor, is found at 3p21.3.38 Although its specific function has not been identified, myristoylation of the protein seems to be necessary for tumour suppression.39 All four of these genes are commonly deleted or inactivated in small-cell-lung-cancer cell lines.40-42 Moreover, transfection of wild-type FHIT,43 RASSF1,44 or FUS1(45) into tumour cells results in restoration of regulatory controls and growth inhibition. The specific gene (or genes) that functions as a tumour suppressor on chromosome 3 has yet to be conclusively characterised.

The TP53 gene encodes a transcription factor that limits cell-cycle progression in the face of genomic damage.31 TP53 mutations are the most common genetic abnormalities in human cancers; they are found in more than 75% of small-cell lung cancers and cell lines.46 These mutations, whether deletions or point mutations,46 ultimately result in deregulation of cell growth controls and increased rates of proliferation.

The retinoblastoma gene RB1 encodes a nuclear phosphoprotein that helps to regulate cell-cycle progression. Dephosphorylation of the protein leads to progression from G1 to S phase. RB1 inactivation is very common in small-cell lung cancer, with inactivating mutations present in more than 90% of tumours.47

The tumour-suppressor gene PTEN encodes a protein with tyrosine and lipid phosphatase activity.48 Through phosphatase activity on phosphatidylinositol triphosphate, PTEN inhibits the phosphatidylinositol-3-kinase/Akt pathway.48 Mutation or deletion of PTEN can lead to increased activity of the pathway, more rapid cell growth, anchorage independence, and reduced apoptosis. PTEN loss of heterozygosity was found often of 11 small-cell-lung-cancer cell lines and tumours (91%),49 but homozygous deletions were detected in only three of 35 cell lines (8%).50

Presentation and diagnosis

Patients with small-cell lung cancer typically present with disseminated disease. Symptoms are related either to bulky, intrathoracic disease or to distant metastases; cough and dyspnoea are the most common findings (table 2).51 Small-cell lung cancer tends to be centrally located, with hilar masses and hilar and mediastinal adenopathy (figure 1). Bronchoscopy shows submucosal endobronchial lesions, which partly explain the low likelihood of finding tumour cells in cytological brushings or sputum samples.

Diagnosis is typically made by histological analysis of a bronchoscopic biopsy sample, or by cytological study of percutaneous or transbronchial fine-needle aspiration samples.52-54 In the WHO 1999 classification system,55 small-cell lung cancer is defined as "a malignant epithelial tumour consisting of small cells with scant cytoplasm, ill-defined cell borders, finely granular nuclear chromatin, and absent or inconspicuous nucleoli. The cells are round, oval, and spindle-shaped, and nuclear molding is prominent. The mitotic count is high" (figure 2). The classification of small-cell lung cancers has been simplified into two categories; more than 90% are typical small-cell lung cancers. The remainder are recognised as combined small-cell carcinoma-combined with any of the histological subtypes of non-small-cell lung cancer. Typically, this combination involves adenocarcinoma, squamous-cell carcinoma, or large-cell carcinoma, though spindle cells or giant cells are observed.55 Review of SEER registry lung-cancer cases showed 94% consistency between registry-reported histological diagnoses and independent reference pathologists.56 However, because small-cell samples can be vulnerable to crush artifact from biopsy foreceps and distortion on fine-needle aspiration, differentiation from non-small-cell lung cancer can be difficult in some cases. Though immunohistochemical analysis is not generally necessary for a diagnosis, these stains can be helpful in difficult cases. Epithelial markers such as cytokeratins are ubiquitous in these tumours and help to distinguish them from lymphomas. Furthermore, chromogranin, synaptophysin, and CD56, all neuroendocrine markers, can be useful in differentiating small-cell from non-small-cell lung cancer.

Paraneoplastic syndromes

Small-cell lung carcinoma has long been associated with paraneoplastic syndromes. The endocrine paraneoplastic disorders are characterised by ectopic production of peptide hormones, and the neurological complications are related to antibody-mediated damage to the central nervous system (table 3).

Hyponatraemia can be found in up to 15% of patients with small-cell lung cancer at presentation.57 In many of these patients, ectopic production of antidiuretic hormone, also known as arginine vasopressin, leads to reduced renal clearance of free water with a subsequent decrease in serum sodium concentrations and the syndrome of inappropriate antidiuretic hormone.58-60 Atrial natriuretic peptide can also be produced ectopically by small-cell lung cancers and might have a role in hyponatraemia of malignancy.58,60,61 The syndrome is characterised by decreasing serum sodium concentrations, which can affect mental status and lead to seizures. Laboratory abnormalities include serum hypo-osmolality, urine osmolality exceeding 100 mmol/kg, and a normal to high urine sodium concentration (>40 mmol/L). The condition improves when the underlying tumour responds to effective treatment. However, other measures might be needed to improve symptomatic hyponatraemia. These measures include saline hydration, loop diuretics, and restriction of free water.62 If needed, demeclocycline can be used to antagonise the effect of ectopic arginine vasopressin at the renal collecting tubule.63

Cushing's syndrome is present in 2-5% of patients with small-cell lung cancer at the time of presentation.64 Common symptoms and signs of the disorder include central obesity, facial plethora, hirsutism, acne, weakness, glucose intolerance, and hypertension. The syndrome is caused by ectopic production of corticotropin by tumour cells. Although more than 50% of small-cell lung cancers produce immunoreactive corticotropin precursors, only 2-5% process the precursor into a biologically active form that elicits the symptoms, signs, and laboratory abnormalities of Cushing's syndrome.65 As well as treatment of the underlying tumour, management of ectopic corticotropin production might necessitate reduction of cortisol synthesis by an adrenal enzyme inhibitor such as ketoconazole.66

Lambert-Eaton myasthenic syndrome is caused by autoantibodies directed against P/Q-type voltage-gated calcium channels.67 Decreased acetycholine release at motor nerve terminals leads to the classic proximal muscle weakness.68 Patients can also experience autonomic symptoms such as dry mouth, constipation, and erectile failure. The diagnosis can be made by autoantibody detection on radioimmunoprecipitation assay.69 Electromyelography characteristically shows increasing amplitude of muscle action potentials with high-frequency stimulation.70

Treatment directed at the underlying small-cell lung cancer generally results in neurological improvement in patients with this syndrome.71 In addition, many of these patients are given 3,4-diaminopyridine. Small studies with this drug have shown significantly increased muscle strength in treated patients;72 as many as 85% of patients treated with 3,4-diaminopyridine experience neurological improvement.71 For patients with severe weakness, intravenous immunoglobulin or plasmapheresis can provide short-term benefit.73,74 For those who do not respond to 3,4-diaminopyridine, prednisone alone or with azathioprine or ciclosporin can help to improve muscle strength and provide long-term control.71

Staging

Patients with small-cell lung cancer rarely present with disease that is sufficiently localised for surgical resection to be possible, so the TNM staging system is generally not used. Instead, staging typically uses the Veterans Administration Lung Study Group system, which classifies patients as having either limited-stage or extensive-stage disease.75 The definition of limited-stage disease varies but is generally designed to include patients whose disease is limited to one hemithorax, with hilar and mediastinal nodes that can be encompassed within one tolerable radiotherapy portal. Extensive-stage disease is any disease beyond those boundaries.

Most (60-70%) patients present with clinically obvious extensive-stage disease. These patients have median survival of 7-12 months and the proportion alive at 5 years is 2%; among patients with limited-stage disease, median survival is about 23 months and the proportion surviving 5 years 12-17%.3,76 Given the prognostic and therapeutic implications, the main goal of staging is to identify sites of disease outside of a potential radiotherapy portal. The ensuing assessment is prompted by the patient's presenting symptoms, as well as by the most likely sites of metastatic involvement (table 4).77

In addition to a history and physical examination, patients typically undergo routine haematological and serum chemistry tests. CT of the chest should be done. Chest imaging allows the extent of intrathoracic involvement to be assessed, including the presence of pleural effusion, lobar collapse, hilar and mediastinal adenopathy, and contralateral parenchymal disease. Fibreoptic bronchoscopy can be used to characterise the disease in the airways and allow the initial diagnosis. The findings are abnormal in more than 90% of cases.54,78

Clinical signs or symptoms should indicate appropriate additional staging. Any clinical evidence of neurological abnormality should prompt MRI or CT of the brain and MRI of the spinal cord, because metastases in the central nervous system will be identified in 80-90% of patients.79,80 A radionuclide bone scan should be done for patients with bony pain. Owing to the frequency of liver metastases (table 4), the chest CT should be extended caudally to include the liver and adrenal glands, if not done already, if results of liver-function tests are abnormal. Follow-up biopsy of hepatic or adrenal lesions should be done if these organs are the only potential site of metastatic disease. For a patient with abnormal complete blood count or peripheral blood smear that cannot be otherwise explained, bone-marrow biopsy should be considered, particularly if there is no other site of extensive-stage disease.

The search for extrathoracic disease can potentially become both exhausting and expensive. In patients for whom locoregional therapy for apparent limited-stage disease is being considered, the assessment should be planned because identification of distant disease could spare patients unnecessary chest radiotherapy or surgery. An assessment should include CT of the liver and adrenal glands, MRI or CT of the brain, and a bone scan. Except in clinical trials, which have more rigorous staging requirements, further staging studies can be omitted if a patient is found to have an unequivocal site of metastatic involvement that confirms extensive-stage disease. The cost of the staging assessment can be reduced by about 40% if it is curtailed in this way.80

The role of positron emission tomography with fluorodeoxyglucose in small-cell lung cancer is still being investigated. Small-cell lung cancers avidly take up fluorodeoxyglucose, and in a small prospective trial this imaging modality could identify metastatic lesions in patients who were thought to have limited-stage disease by standard staging methods.81 However, at

this time, this approach for small-cell lung cancer has not yet become an approved indication for reimbursement in the USA.

Prognostic factors

Several pretreatment characteristics in patients with small-cell lung cancer have been associated with meaningful differences in survival that have also been noted in patients with non-small-cell lung cancer (panel).82-86 The identification of such factors allows physicians and investigators to compare different populations of patients and to interpret the contribution of treatment to differences in survival between different groups. For example, since women with small-cell lung cancer generally outlive male patients,82,83 and because more women are developing lung cancer4 and taking part in clinical trials,83 recent improvements in overall survival for patients with small-cell lung cancer could be due partly to the greater percentage of women in trials rather than a treatment effect, especially in limited-stage disease.

Treatment

Combination chemotherapy remains the cornerstone of treatment for both limited-stage and extensive-stage small-cell lung cancer. In general, the administration of etoposide and cisplatin plus chest radiotherapy for patients with good performance status and limited-stage disease should produce a complete-response rate of 80% or higher, median survival in excess of 17 months, and 5-year cancer-free survival of 12-25%.76,87 Patients with extensive-stage disease given combination chemotherapy should have a complete-response rate of more than 20% and median survival longer than 7 months; in addition, 2% of patients will be alive and without cancer at 5 years.3 The death rate from complications of therapy should be less than 5%.

Surgical resection

Surgery in small-cell lung cancer was largely abandoned in the 1970s because the proportion of patients alive at 5 years was less than 5%.88,89 Sequential phase II studies and case-series reports showed that among patients who underwent surgical resection before a histological diagnosis of small-cell lung cancer and who were given chemotherapy, chest radiotherapy, or both, 5-year survival was 35-40%.90-93 The potential benefits of resection in small-cell lung cancer are predominantly seen in patients with TNM stage I disease. At this point, careful radiological and mediastinal staging should be used to select candidates for surgery. For patients with disease of clinical stage I with peripheral lesions and no hilar or mediastinal nodal involvement, surgical resection is recommended if the patient can tolerate the surgical procedure. Patients who undergo resection for small-cell lung cancer should still receive adjuvant postoperative combination chemotherapy. Patients with hilar or mediastinal involvement should be assessed for combined modality therapy (chest radiotherapy and chemotherapy).

Treatment of limited-stage disease

The treatment of limited-stage disease has evolved over the past few decades. After attempts at surgical resection were abandoned in the 1970s, attention turned to other therapeutic approaches. Small-cell lung cancer had been shown to respond to treatment with alkylating agents but locoregional failure occurred subsequently in up to 80% of cases.94 Attention

turned to chest radiotherapy for patients with disease confined to the lung and mediastinum. Chest radiotherapy as a single modality led to response rates of about 75%,95 effectively controlling disease in the chest and even achieving cure in about 5% of patients with limited-stage disease.94 Clinical efforts have been focused on improving and refining the chemotherapy regimen, as well as combining these regimens with chest radiotherapy.

The initial chemotherapy regimens were primarily based on cyclophosphamide, and the combination of this drug with doxorubicin and vincristine became widely used by the late 1970s. However, this regimen has been replaced with a combination of etoposide and cisplatin. In a large randomised trial, this cisplatin-based regimen conferred median survival of 14.5 months in limited-stage disease compared with 9.7 months for patients assigned cyclophosphamide, epirubicin, and vincristine.96 The etoposide and cisplatin regimen is also associated with less haematological toxicity, and it is more easily combined with chest radiotherapy.87,96,97

The etoposide and cisplatin regimen is typically administered every 3 weeks for four to six cycles. Etoposide is given intravenously at 80-120 mg/m^sup 2^ on days 1, 2, and 3, and cisplatin is administered intravenously at 60-90 mg/m^sup 2^ for 1-3 days starting on day 1.87,97-99 Attempts to improve survival by continuing therapy for longer than six cycles have been largely unsuccessful, with greater toxicity but no survival benefit for patients with limited-stage disease in eight of nine studies.100-103

A meta-analyses of 13 prospective, randomised trials for patients with limited-stage small-cell lung cancer that compared chemotherapy alone or with chest irradiation showed that 5% more patients were alive at 2 years and 3 years in the group assigned chemotherapy and radiotherapy.104 Twice-daily chest radiotherapy to a dose of 45 Gy plus etoposide and cisplatin is favoured over once-daily chest radiotherapy to 45 Gy on the basis of a 10% absolute survival benefit at 5 years.87 Whether higher doses of once-daily chest radiotherapy will be as effective as twice-daily chest radiotherapy and be easier to administer is currently being investigated.

Chest radiotherapy given concurrently with the first or second cycle of chemotherapy has proven superior to sequential radiotherapy.97,105 Therefore, the current recommendation for limited-stage disease at this time is administration of four to six cycles of chemotherapy with etoposide and cisplatin, combined with twice-daily radiation that starts in cycle 1 or 2.

Treatment of extensive-stage disease

Combination chemotherapy remains the focus of treatment for patients with extensive-stage small-cell lung cancer. Radiotherapy in extensive-stage disease is reserved for the prevention106 or treatment107,108 of brain metastases; for symptomatic bone metastases; for cord compression; or for palliative treatment of lobar collapse or superior vena cava syndrome in patients who have not responded to chemotherapy and have not received radiotherapy to those sites. Routine use of chest radiotherapy in extensive-stage disease does not prolong survival.

The combination of cisplatin and etoposide remains the most widely used regimen. The median survival for patients with extensive-stage disease remains at about 7-9 months, and only about 2% of patients survive for 5 years.3,84,96 Other strategies have been studied in

attempts to improve on these results. Changes in the chemotherapy regimen, dose intensity, dose density, schedule, and duration have been investigated.

In a study in Japan, etoposide plus cisplatin was compared with irinotecan plus cisplatin; there was a significant survival advantage with irinotecan in patients with extensive-stage small-cell lung cancer (median survival 12.8 vs 9.4 months; p=0.002).109 The treatment benefit of topoisomerase inhibitors was not seen in subsequent trials in the USA and Europe. In the US trial that compared irinotecan plus cisplatin with etoposide plus cisplatin, there was no significant difference in response rate (48% vs 44%), median time to progression (4.1 vs 4.6 months), median survival (9 vs 10 months), or 1-year survival (35% vs 37%). Patients assigned irinotecan plus cisplatin had less myelosuppression but more diarrhoea than those assigned etoposide plus cisplatin.110 A trial comparing oral topotecan and cisplatin with intravenous etoposide plus cisplatin in a European population also did not show improved efficacy with the topoisomerase inhibitor. The median survival and 1-year survival were similar in both study groups, and time to progression favoured etoposide plus cisplatin.111

Two large randomised trials have investigated the addition of further agents to the standard regimen of etoposide plus cisplatin. In one study, patients were assigned etoposide plus cisplatin with or without ifosfamide.112 The second study compared etoposide plus cisplatin with etoposide, cisplatin, cyclophosphamide, and epirubicin.113 Both trials showed slight survival benefits favouring the regimen with three or four drugs, but at the cost of greater toxicity.

Two trials have specifically investigated the benefit of higher doses of chemotherapy with platinum-based regimens. One, a study of 90 patients with extensive-stage disease, showed no survival difference between the standard-dose and high-dose groups.98 In the other, 105 patients with limited-stage small-cell lung cancer were enrolled, with 2-year survival of 26% in the standard-dose group and 43% in the high-dose group.114 Although two phase II trials on high-dose therapy with autologous bone-marrow transplantation had encouraging results,115,116 the only completed phase III study of high-dose therapy with bone-marrow transplantation found no difference in median survival.117 At this time, higher doses of chemotherapy are not routinely used and remain under investigation.

Etoposide is typically administered intravenously for 3-5 days of a 21-day cycle. It has greater efficacy when given on a 3-5 day schedule than when given on a single day.118,119 Attempts to alter this schedule have largely been unsuccessful. Patients with extensive-stage disease who were treated with 21 days of etoposide did not have any survival advantage over those receiving the drug for 3-5 days.120

Changes in the schedule of the chemotherapy cycle have also been investigated. The use of weekly chemotherapy resulted in greater toxicity with no survival advantage.121,122 Three trials in which the interval between chemotherapy cycles was shortened, with or without growth-factor support, found no consistent benefit for the patients treated.123-125

To avoid the nausea, ototoxic, and nephrotoxic effects of cisplatin, regimens substituting carboplatin have been attempted in both single-group126 and randomised trials.127 To date, the substitution has not led to any significant difference in survival. However, because there is much more information and experience with cisplatin in this disease, especially in combination with chest radiotherapy, the cisplatin and etoposide regimen remains the standard of care.

The duration of chemotherapy has been studied in both limited-stage and extensive-stage small-cell lung cancer. More than ten trials have investigated addition of further chemotherapy after the four to six cycles of induction chemotherapy. This maintenance treatment has included both cytotoxic chemotherapy and targeted agents. Maintenance therapy was associated with greater toxicity without a survival benefit.100-103,128,129

Although alternating chemotherapy regimens were previously of interest,128,130 this strategy has not been superior to a single combination of platinum-based regimens in later trials.131,132 Alternating therapy is not widely used and is not a major focus of current studies.

Various novel targeted agents have been investigated in small-cell lung cancer. These include inhibitors of c-kit,22,23 matrix metalloproteinases,133,134 farnesyl transferase,135 proteosomes,136 and mTOR,137 as well as antiangiogenic agents.138,139 The results of these trials have been largely negative, though further investigation is warranted, particularly of antiangiogenesis and mTOR inhibition.

Additional treatment issues

Prophylactic cranial irradiation

Patients whose small-cell lung cancer has been successfully treated nonetheless have a 50-67% risk of developing metastases in the central nervous system.140,141 Therefore, in patients who have had a complete response to chemotherapy, cranial irradiation is used prophylactically. The radiation is typically administered in doses of 24-46 Gy in eight to 15 fractions. A meta-analysis of randomised trials of prophylactic cranial irradiation showed that the intervention reduced the risk of brain metastases by 45%; moreover, patients assigned prophylactic cranial irradiation were 5% more likely to be alive at 3 years than those not assigned the intervention.106 Though concerns have been raised about possible intellectual impairment with prophylactic cranial irradiation, studies to date have not proven that the intervention is the sole cause. Neuropsychological testing showed most impairment was detectable before administration of prophylactic cranial irradiation. In addition, patients randomly assigned prophylactic cranial irradiation or observation showed no detectable difference in post-treatment neurological function when tested a year later.141 Patients with limited-stage small-cell lung cancer who achieve complete remission should receive prophylactic cranial irradiation. Patients with extensive-stage disease who have complete responses to chemotherapy who are given prophylactic cranial irradiation seem to have longer survival than patients who are not, but the evidence so far is less conclusive.140,141 We recommend that patients with extensive-stage disease and good prognostic factors be offered prophylactic cranial irradiation if they achieve complete remission.

Treatment in patients with poor performance status

Single-agent chemotherapy in elderly patients and those with poor performance status was initially intended to provide a more tolerable treatment option.142 However, in comparisons of single-agent oral etoposide with combination chemotherapy regimens, patients assigned combination regimens not only lived longer but also had fewer side-effects.143,144 Therefore, combination chemotherapy remains the standard treatment in this setting. When the tolerability of standard dose etoposide and cisplatin remains a concern, options include

dose reduction, substitution of carboplatin for cisplatin,145,146 or a combination of low-dose cisplatin, doxorubicin, vincristine, and etoposide.147

Progressive or relapsing disease

Most patients with small-cell lung cancer relapse within a year of starting treatment. The likelihood of response to subsequent therapy can be predicted on the basis of the response to previous therapy and the duration of drug-free interval. Patients who did not respond to previous therapy or who relapsed within 3 months of completing therapy are judged refractory, whereas those who had responded to previous treatment and relapsed 3 months or longer after completing such treatment are deemed sensitive. For patients with sensitive disease, second-line regimens, such as single-agent topotecan or the combination of cyclophosphamide, doxorubicin, and vincristine yield response rates of about 20%, with median survival times of about 25 weeks.148 For patients with refractory disease, response rates are less good; single-agent topotecan achieves responses in about 8% in this setting.149,150 However, combination chemotherapy based on irinotecan or topotecan for refractory or relapsed small-cell lung cancer has shown more promise. A study of topotecan with cisplatin in 110 patients with relapsed or refractory disease found response rates of 29.4% in sensitive disease and 23.8% in refractory disease.151 Several smaller, single-group studies of combination chemotherapy with regimens based on irinotecan, topotecan, or paclitaxel have documented response rates of 29-80%.152,153 The results of larger randomised clinical trials with these newer regimens are still needed to identify the best treatment for relapsed disease.

Long-term survivors

With the widespread use of combination chemotherapy, a small but important number of patients will achieve long-term survival. After 2 years, the risk of death from the initial disease begins to decrease; by 3 years, the daily hazard drops by a factor often.154 Nonetheless, the hazard ratio remains seven to ten times that of the general population, owing partly to the development of second primary tumours.155-157 The risk of a second primary is 2-10% per patient per year, a risk ten times that of adult male smokers who have not developed lung cancer.156,157 Therefore, these patients are good candidates for participation in screening and chemoprevention trials. Moreover, any new lung masses should be promptly investigated and biopsy samples taken, because they might be surgically resectable second primary tumours.

Further information

Clinical guidelines for the treatment of small-cell lung cancer have been established by several national and international committees. For further reference, the recommendations of the National Comprehensive Cancer Network158 and the European Society for Medical Oncology can be reviewed online.159

Conflict of interest statement

Bruce E Johnson has received an unrestricted gift from Genentech. David M Jackman declares that he has no conflict of interest.

Sidebar

Search strategy and selection criteria

This seminar is based mainly on papers published during the past 5 years, although some classic papers have been cited. The search strategy selected articles from MEDLINE by use of the PubMed system. The key words used were "carcinoma, small cell lung" cross-referenced with key words such as "epidemiology", "pathology", "cytogenetics", "molecular biology", "diagnosis", "antineoplastic agents", "radiotherapy", and "surgery". Only papers with an abstract in English were considered.

References

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AuthorAffiliation

Dana Farber Cancer Institute and Department of Medicine, Brigham and Women's Hospital, Boston, MA, USA (D M Jackman MD, B E Johnson MD)

Correspondence to: Dr David M Jackman, Dana Farber Cancer Institute, 44 Binney Street, Boston, MA 02115, USA

djackman@partners.org

Copyright Lancet Ltd. Oct 15-Oct 21, 2005