Jarushka Naidoo and Oscar S. Breathnach
EPIDEMIOLOGY
Small cell carcinomas are a biologically aggressive subset of neuroendocrine tumors (NETs) that most commonly originate in the lung. These cancers constitute approximately 15% to 20% of all lung carcinomas, the incidence of which is decreasing worldwide. Small cell lung cancer (SCLC) is a disease of the smoking population. Multimodality therapy in SCLC improves survival in patients who exhibit a response to combination chemotherapy. SCLC is highly responsive to chemotherapy, but unfortunately exhibits a high rate of relapse and thus poor prognosis.
PATHOLOGY
The 1999 WHO International Association for the Study of Lung Cancer (IASCLC) classifies SCLC into three groups:
1.Classical small cell carcinoma
2.Large cell neuroendocrine tumor
3.Combination of small cell carcinoma, with areas of non–small cell lung carcinoma (NSCLC)
SCLC is characterized by poor differentiation, elevated mitotic rate, and a high proliferation index as per the World Health Organisation classification (WHO). Cellular morphology under light microscopy shows small round blue cells with scant cytoplasm, fine granular chromatin, and indistinct nucleoli.
Immunohistochemical stains indicating the presence of small cell carcinoma include:
–Keratin
–Tissue transcription factor-1 (TTF-1)
–Epithelial membrane antigen
Immunohistochemical markers of neuroendocrine differentiation include:
–Synaptophysin
–Chromogranin
–Neuron-specific enolase
Thirty percent of SCLC biopsies can contain NSCLC, thus leading to the hypothesis that lung carcinoma originates from a pluripotent stem cell. NSCLC can co-express the above markers in up to 10% of cases, and lead to diagnostic challenges.
GENETIC ABNORMALITIES
The most commonly observed genetic mutations in SCLC include
–p53 (75% to 95% SCLCs)
–10q and 9p loss of heterozygosity (PTEN site)
–3p deletion (loss of tumor suppressor genes)
–Loss of Rb genes (60% of SCLCs)
–Telomerase enzyme activity is present in 90% of SCLCs. Telomerase functions to stabilize telomere length and resultant cellular immortality. This enzyme is usually present in cells with the ability to divide indefinitely, such as hematopoietic cells and basal epidermoid cells.
–C-kit and phosphorylated C-kit (80% to 90% of SCLCs)
–Kras and p16 mutations are uncommon
CLINICAL PRESENTATION
Seventy percent of SCLCs are metastatic at diagnosis. Patients can either present with symptoms related to the primary tumor or sites of metastatic disease. SCLCs are classically central in location, and present with symptoms such as cough, shortness of breath, or signs of post obstructive infection. Commonest sites of metastasis include the liver, adrenal glands, bone, and brain, and can cause clinical symptoms of bone pain, weight loss, general physical decline, and neurologic symptoms. SCLC is associated with a number of clinical syndromes caused by the production of paraneoplastic antibodies. These syndromes, termed “paraneoplastic syndromes,” confer a poor prognosis, and include:
–Eaton-Lambert myasthenic syndrome (anti-Hu antibodies against voltage-gated calcium channels)
–Syndrome of inappropriate antidiuretic hormone (ADH excess)
–Ectopic ACTH production (Cushing’s syndrome)
–Ectopic parathyroid hormone production
–Sensory neuropathy
–Paraneoplastic encephalomyelitis
The presence of antibodies can be tested in the blood to diagnose the above syndromes. Weight loss is also postulated to be a paraneoplastic phenomenon.
STAGING
Two staging systems exist for SCLC:
1.Veteran’s Administration Lung Group
–This group divides SCLC into two stages: Limited stage and extensive stage.
–Limited stage (LS) SCLC is defined as disease that is encompassed safely into one radiation field. This usually involves disease confined to one hemithorax. Contralateral mediastinal and ipsilateral supraclavicular lymphadenopathy usually do not preclude a diagnosis of limited stage disease.
–Extensive stage (ES) disease is SCLC that has spread outside one of hemithorax, contralateral mediastinal lymph nodes, and ipsilateral supraclavicular lymph nodes. This usually refers to patients with distant metastases, or a cytologically confirmed malignant pleural or pericardial effusion.
–LS SCLC is usually treated with combined chemotherapy and thoracic radiotherapy, with curative intent.
–ES SCLC is not curable, and is thus treated with palliative chemotherapy alone.
2.International Association for Lung Cancer
–This consists of a TNM-based staging system.
–Patients without distant metastatic disease are treated as limited stage disease.
Staging workup usually consists of the following:
–History and physical examination
–CT thorax/abdomen (including adrenal glands)
–CT or MRI brain
–+/– Isotope bone scan
IMAGING
CT or MRI brain scans are important as 10% to 15% of SCLCs have brain metastases at presentation, and early detection and treatment have been shown to improve both patient morbidity and mortality.
The use of positron emission tomography (PET) in the staging of SCLC is a controversial topic. Two studies by Fischer et al. demonstrated that PET/CT had a sensitivity and specificity of 93% and 100% compared to 79% and 100% with standard staging. The rate of upstaging from LS to ES SCLC ranged from 0% to 33% in seven studies, with sample sizes of 4 to 63 patients. The main impact of PET/CT was noted in cases of unsuspected lymph node metastases where a change in the treatment volume of thoracic radiotherapy occurred. PET or PET/CT has not demonstrated improved assessment of treatment response compared to conventional imaging, and has not been shown to assist in prognostication of SCLC. However, studies investigating these questions have been small.
PROGNOSTIC FACTORS
Adverse prognostic factors include
–Poor performance status (PS) (Eastern Cooperative Oncology Group PS [ECOG PS] = 3 to 4)
–Weight loss
–High disease burden (high LDH levels)
Favorable prognostic factors in limited stage disease include
–Female gender
–Normal LDH
–Stage I disease
Favorable prognostic factors in metastatic disease include
–One metastatic site
–Normal LDH
SURVIVAL
Median overall survival (OS) for treated LS SCLC is 15 to 20 months, and treated ES SCLC is 8 to 13 months. Median OS for untreated extensive stage disease is 6 weeks. The 2-year survival for LS SCLC is 20% to 40% and <5% for ES SCLC. The median survival of patients with platinum-refractory or resistant disease is 7 and 30 weeks.
TREATMENT
Limited Stage SCLC
LS SCLC is treated with combined chemotherapy and thoracic radiotherapy. SCLC is an extremely chemosensitive tumor, and combination therapy produces 80% to 90% response rates, and 50% to 60% CR rates.
Chemotherapy
The most commonly used chemotherapy consists of a combination of cisplatin and etoposide (EP or PE regimen) due to high response rates and adequate tolerability. Carboplatin can be substituted for cisplatin in patients with a borderline ECOG PS (2 to 3). However, due to an increased risk of myelosuppression, cisplatin is preferred to carboplatin in LS SCLC, unless cisplatin is contraindicated or poorly tolerated.
Thoracic Radiotherapy
Patients treated with chemotherapy alone for LS SCLC have an 80% rate of local recurrence. Thoracic radiotherapy improves OS and reduces the rate of local recurrence. A meta-analysis of thoracic radiotherapy in LS SCLC showed an increase in the rate of local control by 23% (24% to 47%) and a 5% absolute improvement in OS at 2 years (15% to 20.5%).
Thoracic radiotherapy includes all gross tumor volume present on post chemotherapy planning radiologic investigations, and nodal regions present on prechemotherapy staging. Standard treatment consists of single daily fractions of 1.5 to 2.0 Gy 5 days per week for a 6-week period. Accelerated hyperfractionation consists of an increased number of fractions delivered in a shorter time period. These regimens are associated with increased toxicity. A hyperfractionated schedule of 45 Gy, delivered over a period of 3 weeks twice daily, has shown superior survival outcomes, and is the current standard of care. The CALGB 30610 trial aims to compare such a schedule with traditional longer schedules in a head-to-head comparison.
Thoracic radiotherapy can be concurrent, sequential, or have alternating patterns of delivery. Concurrent and alternating patterns have shown improved survival compared to sequential treatment, but at an increased rate of toxicity (pneumonitis, myelosuppression, esophagitis). Patients who receive different chemotherapy regimens to standard EP do not benefit from early radiotherapy. A recent phase III trial investigated the use of standard chemoradiotherapy with cisplatin and etoposide versus daily cisplatin 6 mg/m2/day plus etoposide, and showed higher rates of toxicity, with no difference in local control or OS. Early thoracic radiotherapy delivered concurrently with cycle 1 or 2 of the standard 3-weekly platin-based chemotherapy is the current gold standard.
Extensive Stage SCLC
The chemotherapeutic regimens commonly used in SCLC include (Table 3.1)
–Platinum compounds (cisplatin, carboplatin)
–Podophyllotoxins (etoposide, teniposide)
–Camptothecins (irinotecan, topotecan)
–Alkylating agents (ifosfamide, cyclophosphamide)
–Anthracyclines (doxorubicin, epirubicin, amrubicin)
–Taxanes (paclitaxel, docetaxel)
–Vinca alkaloids (vincristine)
–Gemcitabine
Standard treatment for ES SCLC is palliative chemotherapy. In patients of adequate ECOG PS (>2) the EP regimen is the standard of care. Cisplatin-based treatment has demonstrated superior response rates and OS in some subgroups. A recent meta-analysis of carboplatin versus cisplatin-based chemotherapy in ES SCLC and poor prognosis LS SCLC demonstrated noninferiority of carboplatin-based regimens in terms of response and survival. Significant hematologic toxicity was noted with carboplatin, and gastrointestinal, ototoxicity, and nephrotoxicity were seen with cisplatin. These factors impact the choice of therapy. Multiple trials have explored the possible substitution of etoposide for irinotecan in ES SCLC. A phase III Japanese trial showed higher response rates (84% vs. 66%) and longer median OS (12.8 months vs. 9.4 months) when compared to EP. The IRIS trial compared EP to carboplatin–irinotecan (CI) and showed a higher response rate and improved median survival favoring the irinotecan arm (8.5 months vs. 7.1 months).
The Elderly
Forty percent of patients with SCLC are over the age of 70 years. Combination chemotherapy is associated with higher rates of toxicity in patients with poorer PS and organ reserve. However, elderly patients who are able to tolerate multimodality therapy benefit from this approach. Elderly patients with a poor PS, who are unable to receive standard combined therapy for LS SCLC, may derive palliative and survival benefit from two cycles of chemotherapy with sequential radiotherapy.
Relapsed/Refractory SCLC
Relapsed SCLC is recurrent disease more than 3 months post completion of first-line therapy. Refractory disease refers to recurrent disease during first-line therapy, or within 3 months of treatment completion. Eighty percent of patients with SCLC and nearly all patients with ES SCLC will relapse after first-line therapy. The treatment of relapsed/refractory disease consists of palliative chemotherapy.
Common chemotherapeutic agents used are mentioned above, and are usually given as single agents, with an average response rate of 10% to 25%. The current recommended second-line therapy is single agent topotecan, which when compared to best supportive care in a registration randomized trial, was found to improve both quality of life and survival. Oral and intravenous topotecan shows similar response rates. Topotecan can be used in both the relapsed and refractory settings, with response rates of 11% to 31% and 2% to 7% respectively. A phase III trial comparing CAV (cyclophosphamide, doxorubicin, and vincristine) to topotecan in second line showed similar response rates (18% vs. 24%) and median survival (25 weeks vs. 24.7 weeks). Topotecan was associated with higher rates of thrombocytopenia and anemia, but had improved symptom control and less neutropenia compared to CAV. Risk factors for myelosuppression with topotecan include poorer PS, prior radiotherapy, extensive prior chemotherapy, prior platinum therapy, and renal impairment.
The median OS of relapsed, treated SCLC is 2 to 6 months. For patients with a longer disease-free interval and adequate PS, a rechallenge of initial chemotherapy regimen is reasonable. Response rates for irinotecan are similar to topotecan in patients with sensitive disease (30%) and refractory disease (<10%), with a median survival of 5 to 7 months. Single agent amrubicin has shown promising activity in refractory SCLC, with an overall response rate of 21.3%, median PFS of 3.2 months, and OS of 6 months, with an acceptable toxicity profile.
Surgery
SCLC presents rarely as an isolated lesion (<5% of cases). Patients with stage I SCLC (T1-2NO) can be treated with complete resection (lobectomy + mediastinal lymph node dissection), followed by adjuvant chemotherapy or chemoradiotherapy if mediastinal lymph node stage is negative or positive respectively. This approach yields a 43% to 53% 5-year survival rate. These recommendations are based on retrospective data and single institution studies. Two randomized trials in 1966 and 1994 investigated the role of surgery in SCLC, and did not support the role of surgery as the primary treatment of an isolated or recurrent lesion. These studies were done prior to the use of modern imaging techniques that would likely upstage many of these patients. A randomized trial of stage I SCLC to surgery versus combined chemoradiotherapy has not yet been done, but would be required to answer this clinical question. Adjuvant surgery after first-line chemotherapy (carboplatin/VP16 +/– ifosfamide) with or without radiotherapy was investigated prospectively in 23 patients with stage I to IIIA SCLC. In this study, only patients with a CR or pathologic stage I demonstrated a benefit in terms of local relapse and OS.
Prophylactic Cranial Irradiation
The incidence of brain metastases in SCLC at 2 years is 80%. Brain metastases represent an area of significant morbidity and mortality in SCLC. Prophylactic cranial irradiation (PCI) consists of 5 to 7 fractions of whole-brain radiotherapy delivered to prevent the onset of symptomatic brain metastases. Each treatment consists of 1.5 to 2.0 Gy per fraction. Higher doses (>3.0 Gy), concurrent chemotherapy, and high total radiotherapy doses have been associated with late neurologic toxicity. In LS SCLC, two meta-analyses demonstrated a 25% reduction in the cumulative incidence of brain metastases at 3 years (23% to 58%) and an improvement in 3-year OS with PCI (20.1% vs. 15.3%). In ES SCLC, the NEJM published an EORTC trial that showed those patients who exhibited either a partial or complete response to combination chemotherapy, benefitted from PCI. PCI reduced the incidence of symptomatic brain metastases from 40% to 15% at 1 year, and improved 1-year OS from 13% to 27%. PCI was well tolerated, with the commonest toxicities consisting of headache, nausea, and fatigue. PCI is not recommended for patients with a poor ECOG PS (3 to 4), multiple comorbidities, or impaired cognitive function. PCI is not given concurrently with chemoradiotherapy due to potentially cumulative neurotoxicity.
New Therapeutic Directions
Multiple strategies have been employed to try and improve response rates and survival in SCLC. These include additional agents, dose escalation, dose dense therapies, targeted therapies, and prognostic/predictive biomarkers.
Additional Agents
First Line A recent phase III trial of carboplatin/pemetrexed versus standard EP in first-line ES SCLC demonstrated inferior PFS and OS in the experimental arm. The addition of bevacizumab to standard EP improves PFS but demonstrated no OS benefit. Two phase III trials demonstrated a lack of benefit with the addition of paclitaxel to EP in ES SCLC, with an increase in treatment-related mortality in the experimental arm (6.5% vs. 2.4%). The addition of cyclophosphamide and epirubicin to EP showed an improvement in response rate and a minor improvement in survival, with a significant increase in hematologic toxicity. Ipilumumab, a CTLA4 inhibitor licensed in the treatment of metastatic malignant melanoma, was investigated in a three arm phase II study in first-line ES SCLC. Ipilumumab was administered either in a phased or concurrent basis with carboplatin/paclitaxel, and assessed by PFS, irPFS (immune-related), BORR (best overall response rate), irBORR, survival, and safety. Phased ipilumumab showed an improvement in irPFS, irBORR, and OS. Further studies with this drug are awaited.
Second Line Combination therapy with paclitaxel and carboplatin, doxorubicin, gemcitabine, cisplatin, and ifosfamide has yielded response rates of 25% to 75.3% in the phase II setting. Carboplatin and paclitaxel showed a response rate of 73% and would require further study. Five phase II trials investigated the combination of gemcitabine and irinotecan in the relapsed setting, with response rates ranging from 10% to 50%, and different conclusions reached in terms of therapeutic benefit. Combinations of gemcitabine with vinorelbine or irinotecan did not show any clinical benefit. Ifosfamide has been shown to improve OS and response rate in one trial, but this was not observed in subsequent validation studies. Picoplatin is a cisplatin analog that has shown preclinical activity in phase II studies in platinum-resistant and platinum-sensitive SCLC. It aims to overcome platinum resistance and in the phase II setting for relapsed/refractory disease demonstrated a 15% response rate and 30% disease control rate. The results of a registration trial are awaited.
Maintenance Therapy Maintenance therapy beyond 4 to 6 cycles of chemotherapy has shown a modest benefit in terms of response rate, but no improvement in survival, and significantly worse toxicity. This was demonstrated by Giacconne et al. with 5 versus 12 cycles of CDE (cyclophosphamide, doxorubicin, and etoposide), and Ettinger et al. with CAV and CAV–HEM (alternating with hexamethylamine, etoposide, and methotrexate) in complete responders.
Dose Escalation/Dose Dense Therapy
Increasing the administered dose or reducing the interval between doses achieves higher response rates, but not necessarily a survival advantage in SCLC. One trial that demonstrated an improvement in OS in LS SCLC stratified patients between standard dose PCDE (cisplatin, cyclophosphamide, doxorubicin, etoposide) versus high-dose PCDE (HD-PCDE), which uses 20% higher drug doses on cycle 1. HD-PCDE demonstrated improved response rates (67% vs. 54%) and improvements in 2- and 5-year OS (42% vs. 20% and 26% vs. 8%). Growth factor support with GCSF or GM-CSF was used to support the delivery of higher drug doses. Meta-analyses of dose intensity in trials using CAV/CAE/EP showed small but statistically insignificant improvements in OS in ES SCLC.
Targeted Therapy
Biologic agents targeting novel therapeutic pathways in SCLC include anti-VEGF therapies (bevacizumab), Mtor inhibitors (temsirolimus), tyrosine kinase inhibitors (imatinib and vandetanib), matrix metalloproteinase inhibitors, and antisense oligonucleotide olibmersen. More recently, the use of oral dasatinib, a SRC inhibitor, was found to have no minimal clinical activity in the phase II CALGB 30602 study. The proteosome inhibitor bortezemib showed some activity, and future trials are investigating its use with topotecan in the relapsed/refractory setting. Hypoxia-targeting agent tirapazamine (TPZ) was investigated in a phase II study in combination with cisplatin/etoposide and thoracic radiotherapy in LS SCLC. TPZ demonstrated an improvement in median survival to 22 months, compared to 17 months in the seminal INT-0096 trial that established combined chemoradiotherapy as standard of care on LS SCLC. However, a trial of TPZ in head and neck cancer was terminated early secondary to increased rates of grade 3/4 esophagitis. Further studies to confirm the role of TPZ, and similar agents are awaited.
Biomarkers
ERCC1 (excision repair cross-complementing-1) is a molecular marker that has been shown to predict response to platinum-based chemotherapy in non–small cell lung cancer. High ERCC1 expression by IHC and RT-PCR has been shown by a number of trials to be prognostic in LS SCLC. However, it has not been shown to be predictive of response to therapy. Whole-genome and haplotype analyses have demonstrated that GSS, ABCC2, and XRCC1 single-nucleotide polymorphisms (SNPs) involved in glutathione metabolism and DNA repair pathways are prognostic in SCLC. Clinical applications for these findings are limited by the different methods of evaluating ERCC expression, and the need for further validation studies. Circulating tumor cells (CTCs) and circulating tumor cell clusters or microemboli (CTMs) have been studied as potential prognostic and pharmacodynamic biomarkers in SCLC. One study has shown that CTC number and reduction after one cycle of chemotherapy are independent prognostic markers. Further studies regarding the clinical utility of these tools are required.
FOLLOW-UP/SURVEILLANCE
NCCN (National Cancer Control Network) and other national and organizational guidelines recommend the following algorithms for post treatment follow-up:
1.LS SCLC
–History and physical examination every 3 to 4 months within years 1 to 2 post treatment
–History and physical examination 6 monthly within years 3 to 5 post treatment, annually thereafter
–Chest imaging at the time of history and physical examination (x-ray or CT)
2.ES SCLC
–3 to 6 monthly CT thorax/abdomen year 1 post treatment
–3 to 6 monthly chest x-ray years 2 to 5 post treatment
–3 to 6 monthly history and physical examination by clinician
Focused radiologic and laboratory investigations should be carried out depending on the clinical signs/symptoms of the patient at the time of consultation.
REVIEW QUESTIONS
A 56-year-old male presents with a 2-week history of shortness of breath and hemoptysis. A routine CXR reveals a 4 cm right hilar mass with associated ipsilateral hilar lymphadenopathy. A CT of the thorax, abdomen, and pelvis does not reveal any distant metastases. A bronchoscopy and biopsy reveal small cell carcinoma of the lung.
1.What immunohistochemical staining pattern would be consistent with the above diagnosis?
A.TTF1 positive, CK 7 positive, keratin positive, chromogranin positive, synaptophysin positive
B.TTF1 negative, CK 7 negative, keratin negative, chromogranin negative, synaptophysin negative
C.TTF1 negative, CK 7 negative, keratin positive, chromogranin positive, synaptophysin positive
D.TTF1 positive, CK 7 negative, keratin negative, chromogranin positive, synaptophysin positive
2.What other staging investigation should this patient receive?
A.PET/CT
B.CT or MRI brain
C.Mediastinoscopy
D.Bone marrow aspiration and trephine
3.What stage is this patient’s disease?
A.Stage I
B.Stage IV
C.Limited stage
D.Extensive stage
4.What treatment would you advise for this gentleman’s small cell lung carcinoma
A.Carboplatin AUC 6 day 1 and Etoposide 100 mg/m2 days 1, 2, 3 q 3 weekly × 6
B.Cisplatin 60 mg/m2 day 1 and Etoposide 100 mg/m2 days 1, 2, 3 q 3 weekly × 6
C.Cisplatin 25 mg/m2 days 1, 2, 3 and Etoposide 100 mg/m2 days 1, 2, 3 q 3 weekly × 4 with concurrent thoracic radiotherapy
D.Carboplatin AUC 5 day 1 and Etoposide 100 mg/m2 days 1, 2, 3 q 3 weekly × 4 with sequential thoracic radiotherapy
5.This patient’s CT brain is negative for metastases. Would your treatment plan for this patient include prophylactic cranial irradiation?
A.Yes
B.No
C.Maybe
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