Рак легких

Oxford Textbook of Oncology. Third edition. 2016. Edited by David J. Kerr, Daniel G. Haller, Cornelis J.H. van de Velde, Michael Baumann


Эпидемиология и этиология

Lung cancer remains the leading cause of cancer-related mortality globally with almost 1.6 million deaths worldwide each year. Estimates of 2008 lung cancer incidence and mortality in 40 European countries indicate 391 000 new cases (12.2% of all cancer diagnoses) and 342 000 deaths (19.9% of all cancer-related deaths) [1]. Lung cancer incidence is very variable across Europe with highest incidence in Central and Eastern European countries (Hungary and Poland) and lowest in Portugal and Sweden. The proportion of newly-diagnosed lung cancer patients in women is also highly variable—from approximately 10% in some Central and Eastern European countries to almost 50% in Denmark and Sweden, reflecting social differences in tobacco consumption. Lung cancer incidence and mortality figures show a stable decline in males in almost all countries, whereas the incidence and mortality in females is rising in majority of European countries except some high-risk countries showing stable or declining trends (Denmark, Iceland, UK). The incidence of lung cancer in never-smokers (persons who smoked less than 100 cigarettes in their life) is approximately twoto three-fold higher in females as compared to that in males [2]. Detailed data on trends in incidence of lung cancer in never-smokers are lacking, with some suggestions of slight increase over time.

It is estimated that almost 160 000 new lung cancer diagnoses occurred in the United States in 2013, with declining death rates in males for two decades and recently observed declining trends in death rates in females [3]. Global lung cancer burden is expected to rise as a consequence of increase in tobacco consumption, particularly in Asian countries. Lung cancer remains a devastating disease, with approximately 10–15% five-year survival rates in European countries and North America.

Active tobacco smoking is the prevailing risk factor for lung cancer development. It is estimated that cumulative lifetime lung cancer risk in heavy smokers may reach 30% as compared to less than 1% in never-smokers [4]. Globally, active smoking is responsible for approximately 50–90% of lung cancers in females and 80–95% of lung cancer in males with wide geographical variation. Passive tobacco inhalation is responsible for approximately 20–50% of lung cancer diagnoses in non-smokers. Tobacco smoke contains more than 50 identified carcinogens, including N-nitrosoamines, polycyclic aromatic hydrocarbons (PAHs), benzene, vinyl chloride, arsenic, and chromium [5]. Exposure of bronchial epithelium to these carcinogens leads to formation of DNA adducts and, if not repaired by DNA repair systems, permanent mutations. The spectrum of genetic and epigenetic changes in airway epithelium from smokers is very broad, including oncogene mutations, gene copy number changes, loss of tumour suppressors, and abnormal methylation pattern. Most of these abnormalities persist over time, explaining elevated risk of lung cancer in individuals who quit smoking. Lung cancer risk depends strongly on the duration of tobacco smoking and age of onset as well as on smoking intensity. Use of low tar and filtered cigarettes is not associated with lower lung cancer risk and contributes to observed phenomenon of increasing proportion of lung adenocarcinomas. Deeper inhalation, related to the need to deliver adequate nicotine amounts to nicotine-addicted individuals, leads to higher exposure of peripheral bronchi to smoke from these cigarettes. The risk of lung cancer gradually decreases after quitting smoking to the level of twoto three-fold of the risk of never-smokers. Other means of smoking tobacco, such as pipes or cigars, are also linked to elevated lung cancer risk, albeit this association appears less strong than for cigarettes—relative risks are within the range of two to five as compared to never-smokers.

Occupational carcinogens associated with lung cancer include asbestos, arsenic, beryllium, cadmium, chromium, nickel, silica, radon, vinyl chloride, and fumes from diesel fuels. Higher risk of lung cancer is also observed in individuals exposed to chest radiotherapy, such as survivors of breast cancer or lymphoma. Exposure to these agents is responsible for approximately 10% of lung cancers among males and 5% in females [6]. Chronic exposure to asbestos in industry workers (asbestos mining, construction, insulation, and shipbuilding industry) is associated with approximately 3–10 times the relative risk of lung cancer. The risk associated with asbestos is greatly increased with consumption of tobacco cigarettes. Exposure to radon (radioactive gas which is a decay product of radium 226 and uranium 238) is of a significant concern not only for mine workers but also for indoor air pollution at residential areas abundant in natural radium and uranium in the soil and rocks. While there is no discussion about the former as a risk factor, harmful effects of low-level radiation from indoor radon continue to be debated. Other occupational lung cancer carcinogens are related to a wide range of industries such as ceramics, glass, steel, mining, and chemical manufacturing.

Молекулярная биология

Genetic predisposition to lung cancer is highly complex with involvement of high-penetrance, low-frequency genes and genes with low penetrance occurring with higher frequencies. Lung cancer belongs to the spectrum of tumours found in patients with high-penetrance syndromes such as Li-Fraumeni (germline P53 mutations/deletions), Bloom (germline BLM mutations/deletions), Werner (germline WRN mutations/deletions), and BRCA (germline mutations/deletions of BRCA1 or BRCA2) syndromes. The precise risks of lung cancer development in careers of mutations or deletions in these genes are, however, difficult to estimate due to lack of large-scale molecular epidemiology studies. The majority of studies addressing low penetrance genetic predisposition focus on polymorphic variants of genes that encode enzymes mediating activation, detoxification, or repair of DNA damage caused by tobacco [7]. Most extensively studied phase I (oxidation, reduction, and hydrolysis) and phase II (conjugation) enzymes involved in the metabolism of tobacco carcinogens include CYP1A1, microsomal epoxide hydrolase-1 (mEH/EPHX1), myeloperoxidase (MPO), NAD(P)H quinone oxidoreductase-1 (NQO1), and glutathione S-transferases. Results of these studies revealed several candidate gene polymorphisms associated with significantly elevated or decreased risk of lung cancer with odds ratios typically in the range of 1.5–3, and suggesting important interactions among risk genotypes. Practical implementation of these associations into molecular tests that could be used to support selection of individuals into lung cancer screening programs remains difficult due to large heterogeneity among designs and results of these studies. Other candidate genetic markers of increased susceptibility to lung cancer include genes involved in inflammatory response and cell cycle control.

Intensive research performed during the last ten years with integrative molecular methods such as genome sequencing, comparative genomic hybridization, and transcriptome analysis led to accumulation of a large amount of data on the spectrum of molecular aberrations in lung cancer [8, 9]. Most of lung cancer genomes present hundreds of mutations, deletions/ amplifications, gene rearrangements, and abnormal methylation patterns, a feature typical for cancers arising from exposure to tobacco-related carcinogens. Of those, only a few abnormalities lead to signifi ant activation of cell signalling pathways leading to tumour growth, progression, and dissemination. Growth of lung adenocarcinomas may depend predominantly on a single molecular event, such as activating mutations in epidermal growth factor receptor (EGFR) gene, Kirsten ras sarcoma virus (KRAS) gene, ERBB2 (HER2) gene or rearrangements in ALK, ROS1, or RET oncogenes. These events are frequently non-overlapping and indicate different biological behaviour with distinct proliferation rate and chemoand radio-sensitivity. For example, EGFR mutations indicate a more indolent course of the disease, substantial benefit from EGFR tyrosine kinase inhibitors, increased response rates to chemotherapy and increased radiosensitivity as compared to wild-type EGFR. Activating EGFR mutations and other above-mentioned molecular features fulfill the ‘oncogene addiction’ model and form the basis for the development of predictive molecular assays for particular targeted therapies, used either in clinical practice (EGFR and ALK inhibitors, briefly discussed below) or within clinical trials. These abnormalities are mainly confi ed to genes coding for growth factor receptors, intracellular pathway signaling proteins or transcription factors. The most extensively studied and the most frequent mutation of this type occurs in codons 12, 13, or 61 of the KRAS oncogene, which codes for a GTP-ase involved in signal transduction from tyrosine kinase receptors. Most of the KRAS mutations are G to T transversions resulting in substitution of glycine by either cysteine or valine. KRAS mutations occur in approximately 10–25% of adenocarcinomas (less commonly in squamous cell carcinomas), are associated with smoking history, and are linked with slightly inferior survival or harbour no prognostic signifi ance according to a number of studies performed in operable series of lung cancer patients [10]. With the exception of promising results of a small phase II study that combines the MEK inhibitor selumetinib with docetaxel as second-line therapy of advanced non-small cell lung carcinoma (NSCLC) with KRAS mutations [11], there is currently no effective targeted therapy for patients with tumours showing this mutation.

EGFR mutations are found in tumours from approximately 10–15% of unselected Western and 30–50% of Asian NSCLC patients, more frequently in never or light smokers. These mutations cluster in exon 18–21 of the gene, leading to conformal changes in the ATP-binding pocket of tyrosine kinase portion of the EGFR protein [12]. Most common mutations are small exon 19 deletions or exon 21 point mutations (L858R and L861X), linked with sensitivity to reversible EGFR tyrosine kinase inhibitors such as gefitinib or erlotinib. Rare exon 18 mutations are also associated with sensitivity, whereas exon 20 point mutations and small insertions are linked with resistance to EGFR inhibitors. Exon 20 T790M mutation is the most common mechanism of acquired resistance, which develops after a median of approximately ten months of gefitinib or erlotinib treatment. Clones of cells harboring T790M may be found by sensitive techniques in 30–50% of tumours prior to therapy with reversible EGFR inhibitors and expand during treatment through clonal selection. Current translational and clinical research efforts are directed towards breaking the mechanisms of acquired resistance with novel EGFR inhibitors or molecules aimed at other targets essential for abnormal cell growth.

ALK is a transmembrane protein of insulin-like growth factor receptor superfamily with tyrosine kinase activity. ALK gene rearrangement is found in approximately 3–5% of NSCLCs, almost exclusively in adenocarcinomas. Most frequently, an intracellular portion of ALK tyrosine kinase is fused with an N-terminal portion of microtubule-associated protein-like 4 (EML4), leading to constitutive activation of ALK. More than ten variants of ALK fusion genes have been identified in lung tumours, with EML4 being the most common and KIF5B, TFG, or KLC1less common fusion partners. ALK rearrangement can be detected in tumours by fluorescence in situ hybridization (FISH) break-apart assay or RT-PCR assay. In addition to these two tests, immunohistochemical staining for ALK protein with antibodies specific ally validated for lung cancer appears very promising. The optimal testing methodology to defi e ALK-positive tumours remains to be established, although it should be noted that results of clinical trials with crizotinib, ALK, and MET inhibitor rely on patients with tumours defi ed as positive by the FISH assay. A testing strategy which relies on immunohistochemistry with specific anti-ALK antibodies followed by FISH break-apart assay in immunopositive cases is commonly adopted in many institutions. The less commonly rearranged ROS1 gene (approximately 1–2% of lung adenocarcinomas) codes for a protein of the same family as ALK, showing approximately 50% of amino acid sequence homology in the tyrosine kinase domain. At least ten fusion partners have been described for the ROS1 gene in lung cancer. Several publications suggest the clinical utility of immunohistochemistry to detect ROS1 protein and preselect tumours for FISH testing. Patients with ALK and ROS1 rearrangements are typically younger and tend to have no or limited tobacco smoking history. Both rearrangements are predictive for benefit from specific inhibitors, including crizotinib (approved in patients with ALK-positive NSCLC) and several other agents currently in clinical development.

Recent research on driving molecular aberrations in squamous cell carcinoma identified several candidate genes with mutations or amplifications leading to activation of downstream signalling. From a therapeutic perspective, most promising genetic changes include DDR2 and PIK3CA mutations or FGFR1, SOX2, or PIK3CA amplifications. Several clinical trials with inhibitors of the above targets are ongoing.

Dysregulation of tumour suppressor genes (TSGs) is a common finding in lung cancer. P53 gene mutations are almost universal in small-cell lung carcinoma (SCLC) and occur in approximately half of NSCLCs. P53 protein is involved in several cellular processes, such as DNA repair, cell-cycle and apoptosis control, autophagy, senescence, and ageing. Most P53 mutations are missense and cluster in the DNA-binding domain, resulting in the defective p53 protein not being able to transactivate target genes mediating the above processes. In addition, several P53 mutations are linked with gain-of-function properties typical for dominant oncogenes. Clinically, P53 mutations are associated with worse prognosis of surgically treated NSCLC patients and appear to associate with radioand chemo-resistance. Several strategies to restore functional P53 pathway have been developed and tested in clinical trials. These strategies include retrovirus or adenovirus-mediated gene therapy with wild-type P53 [13], small molecule inhibitors of P53-MDM2 interaction [14], or mutation-specific P53-directed tumour vaccines [15].

Other important TSGs with a relatively high proportion of aberrations (mutations, allele losses, epigenetic modifications) in lung cancer include LKB1, NF1, PTEN, ATM, RB1, FHIT, and APC [8]. Other yet undefined suppressor genes are being unravelled through high-resolution genomic hybridization methods. The diagnostic and therapeutic significance of these abnormalities at present is unknown. Tumours with deleted TSGs may depend on activation of unsuppressed downstream pathways (e.g., loss of LKB1 results in mTOR activation; loss of NF1 results in RAS/RAF/MEK and/ or mTOR activation). Inhibition of these pathways is currently explored in clinical trials.

Патология

The pathology of lung cancer, like the molecular biology of this diverse group of malignant diseases, has become of even greater importance in the approach to diagnosis and treatment of this most common and fatal of malignancies. Traditional pathology is based upon haematoxylin and eosin (H&E)-stained section morphology, underpinning the WHO classification of lung tumours applied to resected cancer specimens. Most pathological tumour diagnosis is, however, made on small biopsy samples or cytology and increasingly, immunohistochemistry is used to resolve diagnostic problems (see below). Therapeutic choices for patients with lung cancer are based on detailed knowledge of tumour pathology, both in the advanced disease setting but also before, during, and after surgical resection. Choice of chemotherapy may be determined by tumour cell type (small cell, squamous cell, and adenocarcinomas are treated differently) as may be genetic investigations to determine molecular targeted therapy. It is now no longer acceptable to classify lung cancer according to a simple dichotomy of small cell carcinoma; yes or no? The ‘category of convenience’ that was NSCLC comprises a number of biologically diverse malignant diseases which are treated in different ways. NSCLC should not be considered a single entity.

In the surgical setting, confirmation of malignancy in small samples is usually required before surgical resection. Intraoperative frozen section diagnosis may be used to inform surgical decision making but full diagnosis and classification of disease is made on the complete resection specimen. The 2015 WHO classification of lung tumours [16] is the standard used and names seven major subtypes of lung carcinoma: squamous cell, adenocarcinoma, large cell, sarcomatoid, adenosquamous, neuroendocrine, and salivary-type carcinomas. The pathology report of the resected tumour should subtype and pathologically stage the tumour according to the TNM system 7th edition [17]. Tumour stage is the major determinant of adjuvant therapy.

Аденокарцинома

Аденокарцинома, видимо, является наиболее распространенным типом рака легких во всем мире, хотя ее доминирование менее выражено в когортах белых, где курение является преобладающим этиологическим фактором. Большинство аденокарцином развиваются в периферической, паренхиматозной части легкого, из прекурсорных поражений атипичной аденоматозной гиперплазии (AAH) и аденокарциномы in situ (AIS, ранее известной как чистая не муциновая бронхиоло-альвеолярная карцинома или BAC). Эти поражения возникают из периферического эпителиального компартмента легких, называемого терминальной респираторной единицей (TRU), характерно экспрессирующих тиреоидный фактор транскрипции 1 (TTF1).

В целом эти опухоли имеют варьирующие размеры и могут быть мультифокальными вследствие либо внутрилегочной экспансии, либо множественных синхронных первичных поражений. Частый смешанный паттерн солидных и «матового стекла» (ground glass) свойств при КТ-сканировании соответствует периферическим участкам опухоли, растущей вдоль альвеолярных стенок без их деструкции (лепидический рост), что приводит к виду «матового стекла» (рис. 46.1).

Типично относительно раннее распространение в локо-региональные лимфоузлы и при распространенном заболевании часто наблюдается лимфангит в легком. Их периферическое расположение и относительная склонность к инвазивному росту, особенно в более агрессивных подтипах, делают частым плевральную инвазию.

Фиг. 46.1. Аденокарцинома c лепидическим паттерном, которая может представлять аденокарциному in situ. Опухолевые клетки растут вокруг альвеол, не разрушая их (H&E x 200).

Фиг. 46.2. Аденокарцинома с ацинарным паттерном, показывающая инвазию в фиброзную строму (H&E x 200).

Существуют 5 основных гистологических паттернов аденокарцином: лепидический (ранее называемый бронхиоло-альвеолярным), ацинарный (рис. 46.2), папиллярный, микропапиллярный и солидый с муцином. Большинство аденокарцином легких показывают микст двух или более этих паттернов. В случаях резекции, опухоли, демонстрирующие преимущественно лепидическую картину, имеют относительно хороший прогноз, другие, которые являются преимущественно микропапиллярными (рис. 46.3) или солидными, показывают значительно более короткую послеоперационную выживаемость с большим риском рецидива. По определению, все аденокарциномы показывают железистые клетки и архитектуру, и в некоторых случаях продуцируют большие количества муцинов и включают муцигенные опухолевые клетки.

Некоторые муцинозные аденокарциномы легкого имеют тенденцию распространяться в легком, с разрушением или без разрушения ткани, с меньшей склонностью к отдаленным метастазам. Эти случаи ранее классифицировались как «муцинозные BAC» и часто несут мутации гена KRAS. Аденокарциномы, особенно развивающиеся у некурящих, часто несут определенную мутацию онкогенов. Многие из этих мутаций оказываются взаимоисключающими (мутации EGFR, KRAS, BRAF и HER2 и перестройка ALK гена), что предполагает биологическое значение и так называемую онкогенную зависимость. Терапевтическое значение этих мутаций обсуждается выше. Некоторые из этих мутаций связаны с конкретными гистологическими особенностями аденокарцином.

Плоскоклеточная карцинома

In general, this type of lung cancer is the second most prevalent, after adenocarcinoma, though where smoking-induced cancers predominate it may remain the most common type. The archetypal form of the so-called bronchogenic lung carcinoma most commonly arises from the epithelium of central large bronchi, transformed by tobacco carcinogens. Progenitor lesions are well recognized; basal cell hyperplasia/squamous metaplasia gives rise to squamous dysplasia and squamous carcinoma in situ, wherein invasive disease develops. Most squamous cell carcinomas (SCC) are destructive growths which cause early bronchial obstruction and various degrees of obstructive pneumonia. Squamous cell carcinomas arising from smaller, more peripheral airways may be becoming more prevalent, presenting as peripheral solitary nodules akin to adenocarcinoma.

Histologically, these tumours are defi ed by the presence of squamous differentiation (keratin or intercellular bridge formation) (Figure 46.4) and most cases are relatively poorly differentiated. Invasive growth is often accompanied by a fibrous stroma and inflammation is variable. Endobronchial growth may have a papillary architecture whilst some peripheral SCCs grow within alveolar air spaces causing relatively little tissue destruction. Some SCCs show areas of tumour with smaller densely packed cells of basaloid morphology—this basaloid variant of SCC (basaloid carcinoma) is a relatively aggressive tumour. Necrosis is common and this may lead to tumour cavitation, although this process is not the preserve of squamous tumours. In general, spread to lymph nodes is a relatively late phenomenon, but these tumours can be extremely aggressive. The frequent association with obstructive pneumonia should demand caution in assuming that lymphadenopathy is malignant, as opposed to reactive, in a case of SCC.

Злокачественные нейроэндокринные опухоли

By far, the most important tumour in this category is small cell lung carcinoma (SCLC). In many countries this tumour is, like squamous cell carcinoma, declining in incidence, probably due to a fall in tobacco consumption, but where smoking remains common, SCLC still accounts for 15–20% of all lung cancers. SCLC tends to be a central, bronchogenic tumour which often presents with bulky central disease, contiguous with hilar and mediastinal lymph node metastases and direct spread into the mediastinum. Peripherally located, small tumours are uncommon, but may account for those rare cases which present with localized, surgically resectable disease. The vast majority of SCLC is stage 4 at presentation. Consequently, most contemporary pathological experience of SCLC is in small biopsy or cytopathology diagnosis.

Fig. 46.3. A surgically resected adenocarcinoma showing predominance of this micropapillary pattern has a relatively poor post-operative survival (H&E x 200).

Fig. 46.4. Squamous cell carcinoma in a lung core biopsy. Keratinization and intercellular bridges are evident so a confident diagnosis can be made (H&E x 200).

Fig. 46.5. Small cell lung carcinoma in a core biopsy of a paraspinal metastatic deposit (H&E x 200).

Fig. 46.6. Typical carcinoid tumour showing regular islands of small cells and abundant cytoplasm. (H&E x 200).

These tumours comprise sheets of highly invasive, relatively small malignant cells whose nuclear features (stippled chromatin, moulding) are key to diagnosis. Necrosis, apoptosis, and mitotic activity are all abundant (Figure 46.5). Diagnosis is usually easy by H&E stains and immunohistochemical evidence of neuroendocrine differentiation is not a prerequisite. Sometimes, SCLC may coexist with other forms of NSCLC in the same lesion where, regardless of the amount of SCLC, a diagnosis of combined SCLC is made, and should be treated as SCLC.

Other forms of malignant neuroendocrine tumour (NET) of the lung are much less common than SCLC. Large cell neuroendocrine carcinoma (LCNEC) is another high-grade, aggressive tumour which may arise centrally or peripherally and has an equally poor prognosis to SCLC, at least in surgically resected series. This is a difficult diagnosis to confirm in small diagnostic samples, so the behaviour of LCNEC in the advanced disease setting is not clear. Many cases may be diagnosed as SCLC in small samples but awareness of this tumour type is increasing. Lesions comprise large tumour cells in prominent ‘organoid’ or ‘neuroendocrine’ architecture. Unlike SCLC, tumour cells usually have large, obvious nucleoli and abundant cytoplasm.

Carcinoid tumours are rare malignant neuroendocrine tumours which most often arise in central bronchi, grow slowly and often present with obstructive bronchial symptoms. Most are low-grade, so-called typical carcinoid tumours (Figure 46.6). Regional lymph node metastases are found in around 10% of cases; distant metastases are very rare. Atypical carcinoid tumours are morphologically very similar to typical tumours but for the presence of tumour necrosis and/or a slightly higher mitotic rate (between 2–10 mitoses per 2 mm2 tumour). These are extremely rare tumours with a biological behaviour and post-surgical prognosis similar to SCC.

Типичные карциноидные опухоли с веретеноклеточной морфологией могут развиваться на периферии легкого.

Крупноклеточные карциномы

With the revision of definitions under the 2015 WHO classification, large cell carcinomas (LCC) account for around 4% of resected lung cancers and are defined by the absence of differentiated histological features (squamous or adenocarcinoma) anywhere in the tumours, and a lack of immunohistochemical features which may be associated with SCC or adenocarcinoma (Figure 46.7). This definition is important since it determines the fact that this tumour type can only be diagnosed in the surgical resection setting, when the whole lesion may be examined to exclude squamous or glandular differentiation somewhere in the lesion. These may be central or peripheral tumours, are generally aggressive, invasive, and molecular evidence supports that at least a proportion represents de-differentiated squamous cell or adenocarcinomas.

Саркоматоидные карциномы

These tumours are diagnosed with certainty only in the surgically resected specimens, when more than 10% of the lesion shows spindle, pleomorphic, or tumour giant cells (Figure 46.8). The remainder of the tumour may be undifferentiated or show squamous cell or adenocarcinoma. Extremely aggressive and invasive, such histological features may be recognized and at least described in small sample diagnosis.

Fig. 46.7. This resected lung carcinoma shows large undifferentiated cells and abundant mitoses. In the absence of morphological differentiation, a diagnosis of large cell carcinoma is appropriate (H&E x 200).

Fig. 46.8. This resected lung carcinoma showed evidence of squamous cell carcinoma but also, over 10% of the lesion showed these pleomorphic tumour giant cells, mandating a diagnosis of sarcomatoid carcinoma (H&E x 200).

Аденосквамозная и другие смешанные опухоли

Tumours showing at least 10% of each lesion as clear-cut squamous cell and adenocarcinoma are diagnosed as adenosquamous carcinoma. This is the best known of the combined lung cancer subtypes but is actually quite rare, if diagnostic criteria are strictly followed. They are usually peripherally located and may carry a relatively poor prognosis and represent another diagnosis that should only be offered in surgically resected cases. Other combinations may be encountered; adenocarcinoma with LCNEC is worthy of mention.

Карциномы саливаторного типа

These are extremely uncommon, and are found mostly in the trachea and main bronchi. They are the histological counterparts of adenoid cystic and mucoepidermoid carcinomas better known in the salivary glands and probably arise in the large airway seromucous glands.

Диагностика по небольшим образцам биопсии и цитологии

Большинство пациентов с раком легкого презентует болезнь на поздних стадиях и не имеют истории резецированной опухоли. Единственным материалом, доступным для диагностики, субтипирования опухолей и молекулярного анализа, является небольшой образец биопсии или цитологии (рис. 46.9). Субтипирование опухолей в этой ситуации может быть трудным и неточным, поскольку большинство раковых заболеваний легких содержат большие участки недифференцированной опухоли без признаков дифференцирования, присутствующих в других частях, которые предопределяли бы окончательный полный диагноз, если они забраны, или если все поражение может быть исследовано.

SCLC надежно, неизменно и точно диагностируется в небольших образцах, но диагноз плоскоклеточной и аденокарциномы H&E морфологией может быть неточным и неизменным. Крупноклеточные, саркоматоидные и смешанные карциномы, по определению, не могут диагностироваться неизменно и точно на таком материале. Карциноидные опухоли могут быть распознаны, но обычно их нельзя описать типичными или атипичными категориями, тогда как опухоли слюнных типов могут быть распознаны в хороших образцах.

Problems in recognizing a proportion of squamous cell and adenocarcinomas in small diagnostic samples led to the reasonable practice of diagnosing those cases where only undifferentiated carcinoma has been sampled as NSCLC not otherwise specified (NSCLC-NOS). This diagnosis may account for 20–40% of cases, depending on case mix, sample type, and pathologist experience or bias. The majority of NSCLC-NOS specimens are derived from differentiated tumours which have been poorly sampled; mostly adenocarcinomas. The need for more accurate subtyping has driven the use of immunohistochemistry (IHC) to predict the tumour subtype (IHC positive for p63, cytokeratin 5/6 or p40 predicts squamous cell carcinoma, TTF1 predicts adenocarcinoma) (Figure 46.10). This approach can accurately predict subtype in over 80% of cases, reducing the NSCLC-NOS rate to below 10%, a figure which cannot be reduced further, given the prevalence of large cell and sarcomatoid carcinomas in an unselected lung cancer population.

Симптомы

Increasing number of asymptomatic lung cancer patients are diagnosed with modern imaging techniques performed due to other indications. Typical symptoms from centrally located lung cancer include haemoptysis, cough, wheezing, dyspnoea, chest pain, and frequent lung infections due to atelectasis. Peripheral lesion may be manifested by cough, pain due to invasion of chest wall, and dyspnoea. Tumours located in the superior sulcus are frequently associated with shoulder pain irradiating to forearm, fourth, and fifth fingers. Involvement of the lower brachial plexus is sometimes present with various degrees of neurological deficit. Horner’s syndrome (myosis, ptosis, enophthalmos, and anhydrosis) is due to direct involvement of sympathetic chain. Mediastinal invasion may cause superior vena cava syndrome (SVCS) [18], dysphagia due to oesophageal compression or phrenic nerve palsy. Tumours or lymph nodes located at the aorto-pulmonary window typically result in hoarseness of voice due to recurrent laryngeal nerve palsy. Pleural involvement frequently results in accumulation of pleural fluid and dyspnoea. Occasionally, no primary tumour is present in radiological examinations of these patients, mimicking a clinical picture of mesothelioma. Pericardial involvement is a relatively infrequent but important cause of dyspnoea and other symptoms of cardiac tamponade. These two latter presentations are more frequent in patients with tumours harbouring ALK translocations [19].

Fig. 46.9. (A) This cytology cell block of a pleural fluid shows abundant, large cells of metastatic lung adenocarcinoma. These are in a clear majority of the cells in the fluid and numerous—adequate for molecular testing (H&E x 200). (B) This sample of bronchial washings shows a lot of debris, inflammatory cells but only a tiny cluster of tumour cells (bottom left). These were TTF1 positive but molecular testing would be very problematic on a sample like this (H&E x 200).

Fig. 46.10. (A) Mediastinal lymph node biopsy showing undifferentiated carcinoma lacking features to diagnose squamous cell or adenocarcinoma. This is NSCLC-NOS. Immunohistochemistry (B) shows strong TTF1 positivity so the diagnosis may be refined to ‘NSCLC, probably adenocarcinoma’ (Ч 200). (C) Lung core biopsy showing undifferentiated carcinoma lacking features to diagnose squamous cell or adenocarcinoma. This is NSCLC-NOS. Immunohistochemistry (D) shows strong p63 staining so the diagnosis may be refined to ‘NSCLC, probably squamous cell carcinoma’ (Ч 200).

A proportion of patients presents with symptoms resulting from metastatic spread. Brain metastases may lead to symptoms of increased intracranial pressure, seizures, or focal neurologic deficits. Bone metastases may cause pain and pathological fractures. An adrenal mass may occasionally be misdiagnosed as primary adrenal gland malignancy.

Lung cancer is relatively frequently associated with paraneoplastic syndromes [20]. Most common syndromes include syndrome of inappropriate antidiuretic hormone (ADH) excretion (SIADH), Cushing syndrome, hypercalcaemia due to production of parathyroid hormone-related protein (PTH-rp), carcinoid syndrome, neurological syndromes, hypertrophic pulmonary osteoarthropathy, and venous thromboembolism.

Диагноз и стадийность

Diagnostic workup of patients with suspected lung cancer should include chest radiograms and computed tomography scans of the chest and upper abdomen. Pathological diagnosis remains the cornerstone of lung cancer management in all stages. For centrally located lesions, fibreoptic bronchoscopy (FOB) with forceps biopsy and brush cytology is recommended as a first step to establish tissue diagnosis. Careful description of bronchoscopic findings is essential for consideration of future surgery or definitive radiotherapy. Cytological examination of sputum is currently less frequently performed due to relatively low diagnostic accuracy. Peripheral lesions are accessible through fine needle aspiration, core needle biopsy, or video-assisted thoracic surgery (VATS), which should establish the diagnosis in 90–95% of cases in experienced hands. Although cytological diagnosis remains a valid proof of malignancy, histological diagnosis should be obtained whenever possible to ascertain precise histological subtyping. In patients with pleural effusions, inspection of pleural space through videothoracoscopy with biopsies of suspected lesions and cytological examination of pleural fluid should be performed. This procedure is often combined with pleurodesis to prevent further episodes of symptomatic accumulation of fluid in the pleural cavity.

Use of 18-fluorodeoxyglucose (FDG) positron emission tomography integrated with computed tomography (FDG PET/CT) has changed the paradigm of lung cancer staging. FDG PET/CT is currently indicated in all lung cancer patients with no overt dissemination, who are potential candidates for treatment with curative intent—surgery, radiotherapy, or combined chemoradiation. In a randomized clinical trial of FDG PET/CT versus conventional staging, a significant reduction of futile thoracotomies of about 20% was observed [21]. FDG PET is sensitive, but not very specific, for determination of the malignant nature of the primary lesion. According to two meta-analyses, sensitivity and specificity of FDG PET is around 95% and 80%, respectively [22, 23]. Adenocarcinomas with bronchioalveolar component, carcinoids, and salivary gland carcinomas may show low tracer uptake, whereas squamous cell carcinomas are characterized by relatively high standardized uptake values (SUVs) [24]. Tumours less than 1 cm in diameter may show low FDG uptake due to the effect of respiratory motion and low PET spatial resolution.

FDG PET/CT is particularly useful for nodal staging and outperforms conventional CT in terms of diagnostic accuracy. Recent systematic review and meta-analysis of FDG PET/CT for mediastinal lymph node staging indicated pooled sensitivity of 76% and specificity of 88% (patient-based data) [25], which is higher than those formerly reported for conventional CT. High negative predictive value (NPV) of FDG PET/CT exceeding 90% for mediastinal lymph node involvement in most reports indicate that stage I patients with negative mediastinal scan results do not need to undergo invasive mediastinal staging. Due to the relatively high rate of false-positive FDG PET/CT, results of approximately 10–20%, endoscopic biopsies or mediastinoscopy should be undertaken to confirm N2 or N3 disease with the exception of large, radiologically evident metastatic lymph nodes present on CT scans.

Mediastinoscopy, a short surgical procedure done under general anaesthesia, remains standard to assess paratracheal and subcarinal lymph node stations (stations 2–4 and 7 according to International Association for the Study of Lung Cancer (IASLC) nodal classification) [26]. At present, endobronchial ultrasound-guided fi e needle aspiration (EBUS-FNA) and transoesophageal endoscopic ultrasound-guided fine needle aspiration (EUS-FNA) have largely replaced mediastinoscopy for initial staging of the mediastinum in lung cancer patients and are considered appropriate for invasive staging of the mediastinum. These techniques can assess a wider range of lymph node stations than mediastinoscopy (EBUS: stations 2–4, 7, 10–12; EUS: stations 2L, 4L, 5, 7, 8, and 9). In the largest randomized trial [27] that compared endoscopic staging with mediastinoscopy, sensitivity to detect lymph node metastases was 79% and 85%, respectively (P = 0.47). In patients with mediastinal lymph node involvement who are candidates for radical surgery after induction treatment, mediastinoscopy should be reserved for assessment of lymph node status after initial staging with endoscopic techniques.

The currently used 7th edition of NSCLC TNM staging system was developed by the IASLC based on the database comprising 46 series of patients from collaborative groups and single institutions (a complete dataset of approximately 67 000 subjects) from more than 20 countries worldwide [28]. The staging classification was endorsed by the International Union against Cancer (IUCC) and the American Join Committee on Cancer (AJCC). The T category is subdivided into four subsets (T1–T4) according to tumour size, relationship to anatomical structures in the thorax, occurrence of satellite nodules, and presence of atelectasis (Table 46.1). Regional lymph node metastatic involvement may include N1 (bronchiopulmonary), N2 (ipsilateral mediastinal), or N3 (contralateral hilar, contralateral mediastinal, or supraclavicular) lymph node groups (Table 46.1). A revised map of thoracic lymph node stations was proposed and should be routinely used by pneumonologists, radiologists, thoracic surgeons, radiation oncologists, and all other health care professionals involved in the care of lung cancer patients (Figure 46.11) [29]. The M category is subdivided into M0 (no distant metastases), M1a (satellite lesions in contralateral lung or pleural involvement), or M1b (distant metastases).

Lung cancer stage definitions according to particular T, N, and M categories are shown in Table 46.2. Compared to previous staging system, approximately 15% of patients are placed into different stage categories leading to more accurate associations with outcome [28]. Most notable changes include shift of T3N0 category from previous IIIA to IIB stage group, distinction of satellite nodules in the same lobe as T3 category, in different ipsilateral lobe as T4 category, in the contralateral lobe as M1a category, and shift of pleural involvement from T4 category into M1a category, resulting in a shift of previous stage IIIB patients with this feature into current stage IV. The proportion of NSCLC patients surviving five years from diagnosis according to pathological stage is approximately 60–80% for stage I, 30–50% for stage II, 15–25% for stage III, and below 10% for stage IV, depending on published series.

Лечение немелкоклеточной карциномы легкого ранней стадии

Хирургия

Surgical resection of the lung remains the best treatment for patients with lung cancer whose extension is limited to the primary lesion or to the hilar lymph nodes, provided that the patient has good functional reserve. These patients belong to stage IA, IB, IIA, and IIB. Since the stage IIIA is very heterogeneous, surgery for patients with stage IIIA disease is sometimes controversial. A patient with IIIA disease without mediastinal lymph node involvement (T3N1, T4N0–1) can be considered as a surgical candidate usually in combination with chemoor radiochemotherapy. It should be noted that chemotherapy adds significant, albeit modest, survival benefit. The T4 category ranges from invasion of mediastinal fat tissue to direct invasion to the aorta, or the heart itself. Combined resection of the superior vena cava or left atrium is usually feasible without the aid of cardiopulmonary bypass and sometimes is performed in combination with other modalities of therapy. Resections that require cardiopulmonary bypass are considered to be highly experimental. Treatment for tumours with mediastinal lymph node involvement (N2 disease) is even more controversial. N2 disease is again heterogeneous in clinical outcome when treated by primary surgery. According to Andre et al., five-year survival rate for N2 diseases that were not detected preoperatively involving one lymph node level (‘incidental’ N2) was 34% and those with multiple level involvement was 11%, whereas those that were detected preoperatively with one level involvement was 8% and those with multiple level involvement was 3% [30]. Therefore, single station N2 disease candidates are often considered for surgery, usually combined with chemo/radiotherapy in clinical practice. As discussed later, it is clear that post-operative adjuvant chemotherapy adds significant and modest survival benefit to stage III patients. However, for patients with N2 disease that were preoperatively diagnosed, there have been no clinical trials that clearly proved the role of pulmonary resection.

Таблица 46.1. Определения T, N, и M дескрипторов 7-ой TNM классификации рака легкого

T (primary tumour)
Tx Primary tumour cannot be assessed, or tumour proven by the presence of malignant cells in sputum or bronchial

washings but not visualized by imaging or bronchoscopy

T0 No evidence of primary tumour
Tis Carcinoma in situ
T1 Tumour ≤3 cm, surrounded by lung or visceral pleura, not more proximal than the lobar bronchusa
T1a Tumour ≤2 cm in greatest dimension
T1b Tumour >2 but ≤3 cm in greatest dimension
T2 Tumour >3 cm but ≤7 cm or tumour with any of the following features (T2 tumours with these features are classified T2a if ≤5 cm):

·         Involves main bronchus, ≥2 cm distal to the carina

·         Invades visceral pleura

·         Associated with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung

T2a Tumour >3 but ≤5 cm in greatest dimension
T2b Tumour >5 but ≤7 cm in greatest dimension
T3 Tumour >7 cm or one that directly invades any of the following: chest wall (including superior sulcus tumours), diaphragm, phrenic nerve, mediastinal pleura, parietal pericardium; or tumour in the main bronchus <2 cm distal to the carinaa but without involvement of the

carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumour nodule(s) in the same lobe

T4 Tumour of any size that invades any of the following: mediastinum, heart, great vessels, trachea, recurrent laryngeal nerve, oesophagus, vertebral body, carina; separate tumour nodule(s) in a different ipsilateral lobe
N (regional lymph nodes)
NX Regional lymph nodes cannot be assessed
N0 No regional node metastasis
N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmonary nodes, including involvement by direct extension
N2 Metastasis in ipsilateral mediastinal and/or subcarinal lymph node(s)
N3 Metastasis in contralateral mediastinal, contralateral hilar, ipsilateral or contralateral scalene, or supraclavicular lymph node(s)
M (distant metastasis)
MX Distant metastasis cannot be assessed
M0 No distant metastasis
M1a Separate tumour nodule(s) in a contralateral lobe; tumour with pleural nodules or malignant pleural (or pericardial) effusionb
M1b Distant metastasis

a The uncommon superficial spreading tumour of any size with its invasive component limited to the bronchial wall, which may extend proximally to the main bronchus, is also classified as T1.

b Most pleural (and pericardial) effusions with lung cancer are due to tumour. In a few patients, however, multiple cytopathologic examinations of pleural (pericardial) fluid are negative for tumour, and the fluid is nonbloody and is not an exudate. Where these elements and clinical judgment dictate that the effusion is not related to the tumour, the effusion should be excluded as a staging element and the patient should be classified as T1, T2, T3, or T4.

Reproduced from Goldstraw P et al., The IASLC Lung Cancer Staging Project: proposals for the revision of the TNM stage groupings in the forthcoming (7th) edition of the TNM classification of malignant tumours, Journal of Thoracic Oncology, Volume 2, Number 8, pp. 706–714, Copyright © 2007 International Association for the Study of Lung Cancer, with permission from Lippincott Williams and Wilkins/Wolters Kluwer Health.

Removal of the affected pulmonary lobe (lobectomy) with mediastinal and hilar lymph node dissection remains a standard procedure. The extent of pulmonary resection is primarily based on the results of randomized trial performed by Lung Cancer Study Group reported in 1995 comparing standard lobectomy with limited resections (segmentectomy or wedge resection) for patients with tumours =3cm and no lymph node involvement [31]. This trial showed a trend toward worse outcomes in the patients with limited resection (one sided P = 0.062) [31].

 

Фиг. 46.11. Карта лимфатических узлов для 7-ой редакции стадийной системы рака легкого.

Таблица 46.2. Стадии, категоризированные согласно T, N, и M дескрипторам 7-ой TNM классификации рака легкого

T/M Подгруппы N0 N1 N2 N3
T1 T1a IA IIA IIIA IIIB
T1b IA IIA IIIA IIIB
T2 T2a IB IIA IIIA IIIB
T2b IIA IIB IIIA IIIB
T3 T3 IIB IIIA IIIA IIIB
T4 T4 IIIA IIIA IIIB IIIB
M1 M1a IV IV IV IV
M1b IV IV IV IV

TLymph node dissection is aimed to provide accurate lymph node staging and possibly therapeutic benefit. Although there is no doubt that lymph node dissection provides best staging, the therapeutic role of lymph node dissection is not clear as there have been limited numbers of phase III trials asking this question and their results have been inconsistent.

Recently, the American College of Surgeons has performed a randomized trial of mediastinal lymph node sampling vs lymph node dissection during pulmonary resection in patients with N0 or N1 non-small cell lung carcinoma [32]. In this trial, 2R, 4R, 7, and 10R lymph nodes for right-sided tumours and 5, 6, 7, and 10L for left-sided tumours were sampled, and when all these nodes were negative, patients were randomized either to perform complete lymph node dissection (dissection group) or to no further sampling (sampling group) [32]. There was no survival difference between two arms; the median survival was 8.1 years for the sampling group and 8.5 years for dissection (P = 0.25) [32]. The extensive sampling procedure makes the interpretation of the results difficult. The authors offered the caveats that these results are not generalizable to patients staged radiographically or those with higher stage tumours [32].

When the tumour is large and is located close to pulmonary hilus, it is not possible to remove the tumour by lobectomy. If surgery is indicated in such cases at all, pneumonectomy needs to be performed. Such indication should be carefully assessed and weighted against radical radiochemotherapy by experienced surgeon in a multidisciplinary team, because pneumonectomy (especially right-sided) may potentially cause significant morbidity and mortality. It is not always possible, but in some cases bronchoplastic procedure such as sleeve lobectomy can replace pneumonectomy without deterioration of long-term survival. For patients with poor pulmonary reserve or those with tumours with a supposedly benign nature, segmentectomy or wedge resection may be selected depending on tumour size, location, malignant potential, and patients’ physiological condition.

Although limited resection is inferior to standard lobectomy, recent innovation of diagnostic imaging has made it possible to diagnose tumours of smaller size and with less opaque (ground glass-like) shadow. For these types of tumours, limited resection may be sufficient. The Japan Clinical Oncology Group prospectively evaluated preoperative thin-section computed tomography for its ability of prediction of non-invasiveness in clinical T1N0M0 peripheral lung tumours [33]. In a group of 545 patients, they concluded that radiological non-invasive peripheral lung adenocarcinoma could be defined as an adenocarcinoma =2.0 cm in diameter with =0.25 cm consolidation to the maximum tumour diameter [33]. Several clinical trials validating limited resection strategies for patients with tumours measuring less than 2 cm are underway.

There are several ways to access the lung during surgery. Posterolateral thoracotomy has been the standard for pulmonary resection in which the incision is about 30 cm in length and it starts at point midway between the medial border of the scapula and the thoracic spine, then it curves a little below the tip of the scapula and turns to run parallel with the ribs and extends to the submammary crease, usually dissecting latissimus and anterior serratus muscle. Recently, some surgeons prefer to use muscle-sparing thoracotomy in which division of latissimus or anterior serratus muscle is avoided. This thoracotomy can be used for most pulmonary surgeries including pneumonectomies or bronchoplastic procedures.

With the advent of appropriate imaging technology, VATS is becoming popular. It is expected that less invasion to the chest wall will result in less pain, shorter hospital stay, and less morbidity. However, recent systematic review evaluating two randomized and 19 non-randomized trials that compared VATS lobectomy with open lobectomy (most of them are through posterolateral thoracotomy) suggested that there was no statistically significant difference between two groups in terms of prolonged air leak, arrhythmia, pneumonia, or mortality [34].

In general, pulmonary resection has become a safe procedure with 30-day mortality below 3%. For example, in 11 663 pulmonary resections performed in Japan in 2004, grade >3 post-operative complication occurred in 523 (4.5%) and 30-day mortality was 0.4% [35]. Complications after lung cancer surgery are mostly related to cardiopulmonary sequelae.

Адъювантная послеоперационная химиотерапия

Results of meta-analysis of adjuvant chemotherapy trials in resected NSCLC published in 1995 provided the first unequivocal evidence favoring such treatment (5% survival improvement) [36]. Since then, several randomized trials have been conducted [37–42]. Most of the trials, summarized in Table 46.3, used cisplatin or carboplatin with new generation cytotoxic agents. In two meta-analyses that included recent adjuvant studies, an approximate 5% absolute survival improvement was indeed observed [43, 44]. The benefit was confined to patients with stage II and stage III disease. In stage IB, only patients with tumours larger than 4 cm appeared to benefit, whereas stage IA patients tended to have worse outcomes with adjuvant treatment. A performance status of 2 was associated with no benefit from adjuvant therapy. Current indications for adjuvant chemotherapy include pathological stage II and III NSCLC patients with complete postsurgical recovery and no contraindications to this therapy due to comorbidities. The use of adjuvant treatment in stage IB patients with larger tumours remains controversial. The benefit is observed irrespectively of gender, age, and histological subtype. Since most of the adjuvant chemotherapy trials used platinum doublets with either vinorelbine or paclitaxel, these agents are commonly used in practice. Survival gain from adjuvant treatment appears to be less pronounced after longer observation in some, but not all, clinical trials, indicating possible impact of long-term toxicities from chemotherapy.

Таблица 46.3. Селективные крупные клинические исследования с адъювантной химиотерапией для немелкоклеточного рака легкого

Trial [ref] Number of patients Chemotherapy agents (number of cycles) Pathological stage Survival probability at 5 years (experimental vs control group) Survival hazard ratio (95% CI) P value
IALT [36] 1865 Cisplatin/etoposide (3–4)

Cisplatin/vinorelbine (3–4)

Cisplatin/vinblastine (3–4)

Cisplatin/vindesine (3–4)

I-III 44–5% vs 40–4% 0.86 (0.76–0.98) <0.03
ALPI [38] 1209 Mitomycin C/vindesine/cisplatin (3) I-III NR (1% absolute benefit) 0.96 (0.81–1.13) 0.96
CALGB 9633

[39]

344 Carboplatin/paclitaxel (4) IB 59% vs 57% 0.83 (0.64–1.08) 0.10
BR.10 [41] 482 Cisplatin/vinorelbine (4) IB-II 69% vs 54% 0.69 (0.52–0.91) 0.009
ANITA [37] 840 Cisplatin/vinorelbine (4) IB-III NR 0.80 (0.66–0.96) 0.017
Japan Lung Cancer Research Group [40] 979 Uracil-tegafur (2 years) I 88% vs 85% 0.72 (0.53–1.00) 0.047

NR, not reported.

Based on the analyses of tumour tissue material from adjuvant chemotherapy trials, several biomarkers were proposed to associate with improved outcomes. Immunohistochemical expression of excision-repair cross-complementary 1 protein (ERCC1, a protein involved in the nucleotide excision repair pathway of DNA damage) appeared most promising for application in routine practice to select patients for adjuvant treatment. High ERCC1 expression was thought to be associated with lack of benefit from (platinum-based) adjuvant chemotherapy. A large validation study performed in the cohort of participant of the IALT adjuvant chemotherapy trial did not confirm the previous observations. No biomarker is currently recommended for use for selection of NSCLC patients to adjuvant therapy outside of clinical trials.

Current clinical research strategies to improve outcomes of NSCLC patients with post-operative adjuvant treatments include the use of targeted therapies in molecularly-selected subsets of patients, use of anti-angiogenic agents or immunotherapeutics, and selection of patients based on molecularly-defined risk scores. Until the results of clinical trials testing these strategies become available, they are not recommended for management of NSCLC patients outside of clinical trials.

Радикальная лучевая терапия

The efficacy of modern conventional radiotherapy in patients with early-stage NSCLC is modest and most of the patients experience local relapse after treatment [45]. Most of the series exploring radical radiotherapy in early-stage NSCLC reported outcomes of those patients who were inoperable due to comorbidities or did not wish to undergo surgery. These patients remain at high risk of death due to other causes, such as chronic obstructive pulmonary disease (COPD) or cardiovascular disease. In patients with node-negative NSCLC, stereotactic radiotherapy (SBRT) is associated with excellent long-term loco-regional control approaching surgical results of at least 70% and usually in the range of 80–95% [46]. The procedure is now widely used in developed countries and was demonstrated to impact on survival of early-stage NSCLC cohorts according to Dutch cancer registry data [47]. Main inclusion criteria for SBRT are pathological proof of malignancy (positive PET scan is acceptable only in patients for whom pathological confirmation is not possible) and outside of clinical trials size of less than 5 cm, location not adjacent to mediastinal structures or main bronchi and lymph node-negative disease as assessed by PET (mandatory). Strict radiotherapy quality control measures must be in place, including assessment of respiratory movement of the tumour during treatment planning and image-guided radiotherapy delivery. There is no universal agreement on the best fractionation schedule, but 54 Gy in three fractions, 55 Gy in five fractions or 60 Gy in eight fractions are commonly used in Europe and North America, or 48 Gy in four fractions in Japan. Current clinical studies are evaluating SBRT in larger or centrally located tumours. The use of sequential or concomitant chemotherapy or targeted agents in patients with early NSCLC treated with SBRT is not recommended. Patients with stage II disease who are not candidates for surgery should be managed outside of clinical trials with conventional definitive radiotherapy or radiochemotherapy, depending on comorbidities.

Лечение локально распространенной немелкоклеточной карциномы легкого

Stage III NSCLC, according to the 7th edition of the AJCC TNM classification, describes a very heterogeneous group of different clinical entities, varying from the T3N1 category of patients to those with ipsilateral (N2) or contralateral (N3) mediastinal lymph node involvement. Management of patients with N2 or N3 lymph node stations involved by the tumour continues to be debated, mainly because of lack of suffi  t evidence from randomized clinical trials regarding particular subsets. Several sub-classifications according to the extent of N2/N3 disease were proposed [48, 49] to formally address this need, yet none have been introduced into routine clinical practice. One of the proposals suggests describing N2/N3 nodal involvement as ‘incidental’ (i.e., unsuspected after careful nodal evaluation with PET and invasive staging), ‘discrete’, or ‘minimal’ when single or multiple normal or moderately enlarged lymph nodes are confirmed at staging and ‘infiltrative’ or ‘bulky’ when large nodes with possible mediastinal infiltration are present [49]. Other classifications emphasize single versus multiple nodal station involvement. Historically, patients with ‘resectable’ stage IIIA N2 disease were treated with surgery and those with ‘unresectable’ IIIA and IIIB disease were treated with definitive radiotherapy. Results of both treatment modalities were unsatisfactory with five-year survival rates of approximately 5–15% [50, 51]. Patients with ‘unsuspected’ mediastinal nodal involvement discovered in post-operative pathological evaluation despite thorough preoperative staging according to current standards represent a relatively minor proportion, probably less than 10% of the operable NSCLC population. These patients should be treated with post-operative chemotherapy, with an expected absolute survival benefit of approximately 5% at five years [44]. The role of post-operative radiotherapy in pN2 patients with complete pathological resection (R0) remains unclear and should be a subject of individual risk/benefit evaluation. According to post-operative radiotherapy (PORT) meta-analysis on the role of adjuvant radiotherapy in surgically treated NSCLC [52, 53] patients with mediastinal nodal involvement had neither clear benefit nor detriment from radiation, whereas a survival detriment was clearly demonstrated for patients with pathological stage I and II. Post-operative radiotherapy resulted in improved local control in approximately half of the trials included in the PORT meta-analysis. Since the results of PORT meta-analysis are based on trials conducted more than two decades ago with outdated radiotherapy techniques, current evidence in support or against post-operative radiotherapy in patients with mediastinal nodal involvement remains weak. An ongoing phase III randomized study, Lung ART, should clarify the role of radiotherapy versus observation in patients with post-operative mediastinal nodal involvement. In the meantime, routine post-operative radiotherapy, typically in the dose of 54 Gy, is recommended in some centres in patients with a high risk of relapse (extracapsular extension or by individual assessment by surgeon), whereas other centres do not advocate this therapy. If chemotherapy and radiotherapy is indicated, chemotherapy should probably be administered sequentially to minimize toxicity [49], although no clear evidence exists regarding this strategy.

In patients who have pathologically proven ‘potentially resectable’ mediastinal lymph node involvement at presentation (‘minimal N2’) and in patients with unresectable stage III NSCLC (‘infiltrative N2’ and N3), the role of chemotherapy remains well established and optimal local treatment remains a matter of discussion. Based on two large randomized phase III trials, the role of surgery in both categories of patients appears minimal. The Integroup 0139 trial conducted in the United States randomly allocated patients with stages T1–3 N2 NSCLC to induction radiochemotherapy (radiation dose of 45 Gy with concurrent cisplatin 50mg/m2 days 1, 8, 29, and 36 and etoposide 50mg/m2 days 1–5 and 29–33) followed by surgery within three to five weeks in non-progressing patients or to definitive radiochemotherapy (radiation dose of 61 Gy, chemotherapy as above). Patients in both groups received two cycles of consolidation chemotherapy. The trial demonstrated no difference in overall survival (OS) (median of 23.6 months in group with surgery vs 22.2 months in group without surgery; HR = 0.87; P = 0.24). Progression-free survival was longer in patients randomized to surgery (median of 12.8 months vs 10.5 months; HR = 0.77; P = 0.017). Early mortality not attributable to lung cancer was higher in the surgical group (8% vs 2%, respectively), particularly after pneumonectomy. In an unplanned post hoc analysis of patients treated with lobectomy vs matched cohort receiving definitive chemoradiation, approximately 10% long-term survival advantage was noted. The authors concluded that potential benefit for patients treated with surgery was offset by increased complications and mortality from tri-modality treatment. The 08941 phase III trial by the EORTC Lung Cancer Group included patients with ‘unresectable N2’ NSCLC, a notable difference from the INT0139 trial discussed above. Patients were treated with three cycles of cisplatin or carboplatin induction chemotherapy doublet, most frequently with gemcitabine or a taxane, and then randomly allocated to surgery vs definitive radiotherapy (60–62.5 Gy to involved primary tumour and mediastinal lymph nodes and 40–46 Gy to uninvolved mediastinum). The response rate to induction treatment was 61%. Compliance with assigned treatment was high (92% and 93%, respectively). There was no survival difference for patients allocated to surgery (median of 16.4 months) as compared to radiotherapy (median of 17.5 months).

Based on the above trials, defi tive radiochemotherapy is considered a standard treatment for most patients with stage III NSCLC. Given the subset results of INT 0139 and relative good long-term outcomes of some phase II trials [54], a few institutions continue to recommend surgery in very carefully selected patients with N2 disease after induction treatment (chemotherapy or concurrent chemoradiation). The decisions regarding the optimal choice and sequence of treatment must be taken by multidisciplinary teams of thoracic surgeons, radiation oncologists, medical oncologists, radiologists, pathologists, and pulmonologists. The additional value of radiotherapy added to chemotherapy in this setting is being uncertain and questioned [55]. Pneumonectomy after induction treatment should be avoided given high mortality rates of this procedure. Treatment should be given in high volume centres experienced in multimodality care.

Definitive radiochemotherapy should optimally consist of concurrent radiation and two cycles of cisplatin-based chemotherapy. Current radiotherapy recommendations in stage III NSCLC define target volumes around the tumour and involved nodal regions with appropriate margins, with no elective mediastinal irradiation [56, 57]. Technical advances in radiotherapy, such as PET-based treatment planning, control of respiratory motion by 4D CT, and image-guided radiotherapy delivery, are extremely important for achieving good outcomes. Radiotherapy plans should be qualitatively evaluated for dose distribution in critical organs, such as lung, oesophagus, spinal cord, heart, and brachial plexus to minimize radiation-induced toxicity. International guidelines are available to assist radiation oncologists in making appropriate choices based on dose distribution within organs at risk [58–60]. To select an optimal dose-distribution of a treatment plan, radiation oncologists should consider these guidelines within the context of the institutional experience and predefined quality control procedures. Minimal standards for defi tive thoracic radiotherapy include 3D conformal radiotherapy planning and image-guided radiotherapy delivery according to the institutional protocol. Intensity modulated radiation therapy (IMRT) is commonly used in order to reduce radiation dose to the lung and oesophagus.

The value of concurrent vs sequential chemotherapy and radiotherapy in stage III NSCLC was tested in several clinical trials.

Meta-analysis of these trials [61] indicated an absolute benefit for concurrent treatment of 4.5% at five years (HR = 0.84, P = 0.004) at the expense of increased G3–4 acute esophageal toxicity (from 4–18%) with no difference regarding acute pulmonary toxicity. Cisplatin-etoposide (at full systemic doses) or cisplatin-vinorelbine (with decreased dose of vinorelbine) remain the most extensively studied regimens. Preliminary results of concurrent treatment with novel agents, such as pemetrexed or cetuximab, do not appear promising, although full results of several studies are awaited. The strategies of induction chemotherapy followed by concurrent radiochemotherapy [62] or concurrent radiochemotherapy followed by consolidation chemotherapy [63] have not led to improvement of survival in stage III NSCLC and are not recommended in a routine care.

In a preliminary report from RTOG 0617 phase III trial, conventionally-fractionated 60 Gy and 74 Gy radiotherapy doses were directly compared [64]. In this factorial design study, patients received concurrent chemotherapy (weekly doses of carboplatin and paclitaxel) and cetuximab or placebo, followed by consolidation treatment. Patients who received higher radiotherapy dose had significantly worse survival (median of 20.3 vs 28.7 months in the control group, P = 0.0007). No survival benefit was observed with the addition of cetuximab. In the RTOG 0617 trial, many centres included only few patients. Potential reasons for the unexpected results may lie in under-reported toxicity and in too-tight target volume margins in the high dose arm of the study. While full explanation of the results of RTOG 0617 awaits clarification, the dose of 60 Gy remains the standard of care with concurrent chemotherapy in stage III NSCLC in many institutions. A considerable number of institutions continue to use higher total radiotherapy doses of 66Gy, often exceeding 2 Gy per fraction (hypofractionation), sometimes with simultaneous integrated boost technique. In patients who are not eligible for concurrent radiochemotherapy due to age or comorbidities, sequential chemotherapy and radiation remains the best option. Those who are not eligible for chemotherapy should be treated with definitive radiotherapy alone.

Hyperfractionated and accelerated treatments were evaluated in a meta-analysis of several trials in non-metastatic NSCLC, most of which assessed different schedules of radiotherapy given alone or after induction chemotherapy. A small, but significant, advantage for accelerated schedules was observed with a 2.5% improvement in five-year survival (HR = 0.88, P = 0.009). Signifi antly better loco-regional outcomes were associated with highly accelerated schedules, emphasizing the importance of overall treatment time. The duration of definitive radiotherapy in stage III NSCLC should thus not be protracted (six weeks or even shorter whenever possible). Results of the CHARTWEL trial [65] indicate that the short overall time of radiotherapy delivery is particularly important in case of patients who received neoadjuvant chemotherapy (still significant proportion of patients treated worldwide) and for large tumours. Sequential schedules with highly accelerated radiotherapy are considered as important clinical research strategies to overcome the limitations of concurrent treatment.

Лечение метастатической немелкоклеточной карциномы легкого

More than half of NSCLC patients are diagnosed with metastatic disease; in addition, the majority of patients treated with curative intent for early or locally advanced disease will eventually relapse and develop metastatic disease. With the exception of a small proportion of patients presenting with oligometastatic disease, the prognosis of patients with stage IV NSCLC is fatal with a median survival of 9–15 months and a one-year survival of 30–58% [66, 67]. Systemic therapy is offered to patients with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2, aiming at prolongation of survival and maintaining quality of life. Therapy is individualized based on histological subtype, molecular pathology, age, comorbidities, expected toxicity, and patient preferences. Selected, practice-changing clinical trials addressing the role of chemotherapy in advanced NSCLC are summarized in Table 46.4. Treatment for patients with metastatic NSCLC has historically consisted of systemic cytotoxic chemotherapy [68]. The identification of distinct subsets of NSCLC driven by specific genetic alterations, predicting for the benefit from targeted therapies, has substantially impacted on therapeutic strategies and improved outcome figures for molecularly-defined subsets of patients. Patients with tumours harbouring an activating mutation of the epidermal growth factor receptor (EGFR) or rearrangement of anaplastic lymphoma kinase (ALK) gene should be managed with an EGFR or ALK tyrosine kinase inhibitor (TKI), respectively. Other molecular aberrations, as for example HER2 and BRAF mutations, ROS1, and RET rearrangements, are amenable to targeted therapy and likely to influence lung cancer therapeutic portfolio in the very near future. For all other molecular subgroups representing the vast majority of NSCLC patients, cytotoxic chemotherapy remains the backbone of first-line treatment.

Лечение пациентами с немелкоклеточной карциномой легкого, не характеризуемой генетической драйверной альтерацией

Химиотерапия первой линии

Chemotherapy prolongs survival as compared to best supportive care, with a meta-analysis reporting a 27% relative reduction in the risk of death equivalent to a 10% improvement in one year survival [69, 70].

Platinum-based combination chemotherapy is considered the standard of care in first-line treatment for patients with good performance status. Third generation cytotoxic agents with documented single-agent activity in NSCLC include vinorelbine, gemcitabine, paclitaxel, docetaxel, irinotecan, and pemetrexed. The addition of a second drug to a single-agent regimen significantly increases the response rate (RR), one-year survival, and median overall survival at the expense of higher toxicity [71]. Three drug regimens further increase RR over two drug regimens, but fail to prolong survival, and are associated with increased toxicity [72].

Three meta-analyses evaluating the role of platinum-based vs platinum-free doublets reported a benefit in one-year survival in favour of platinum-based doublets, albeit of marginal statistical significance. This benefit was shown to be restricted to cisplatin in one analysis, and was absent when platinum-based doublet regimens were compared to third generation platinum-free doublets in another study. Platinum-based treatment was associated with a higher incidence of severe toxicity [73–75].

Three meta-analyses have shown a higher response rates for cisplatin when compared with carboplatin combinations. In the individual patient data meta-analysis of nine randomized trials with almost 3000 patients [76], survival figures with cisplatin regimens were non-significantly better (median survival of 9.1 vs 8.4 months, respectively, P = 0.10). In the subset analysis, significantly superior efficacy was noted in the subgroup of non-squamous tumours and in patients treated with third generation cytotoxics. Cisplatin-based chemotherapy was associated with more nausea and vomiting as well as peripheral neuropathy and renal impairment, while haematological toxicity was higher with carboplatin [76–78].

Таблица 46.4. Селективные крупные, изменяющие практику клинические исследования III фазы химиотерапии или иммунотерапии (первая линия, поддержание и вторая линия) для распространенного немелкоклеточного рака легкого

Trial [ref] (setting) Treatment arms Number of patients Median progression-free survival [months] (95% CI)

Hazard ratio (95% CI; P-value)

Median survival [months] (95% CI)

Hazard ratio (95% CI; P-value)

Big Lung Trial [68] (first-line) Cisplatin-based chemotherapy vs

best supportive care

725 NR 8.0 vs. 5.7

HR 0.77 (0.66–0.89; P = 0.0006)

Schiller et al. [66] Cisplatin and paclitaxel 1115 Time to progression 7.8 (7.0–8.9)
(first-line) Cisplatin and gemcitabine 3.4 (2.8–3.9) 8.1 (7.2–9.4)
Cisplatin and docetaxel 4.2 (3.7–4.8) 7.4 (6.6–8.8)
Carboplatin and paclitaxel 3.7 (2.9–4.2) 8.1 (7.0–9.5)
3.1 (2.8–3.9)
Scagliotti et al. [79] Cisplatin and pemetrexed vs cisplatin and gemcitabine 1725 Overall:

4.8 vs 5.1

HR = 1.04 (0.94–1.15)

Overall: 10.3 vs 10.3
(first-line) HR = 0.94 (0.84 to 1.05) Squamous: 9.4 vs
10.8 HR = 1.23 (1.00–1.51, P = 0.05)
Non-squamous: 11.8 vs 10.4 HR = 0.81
(0.70–0.94, P = 0.005)
PARAMOUNT [91]

(maintenance)

Pemetrexed maintenance vs placebo

(in patients non-progressive after 4 cycles cisplatin and pemetrexed, non-squamous tumours)

539 4.1 vs 2.8 HR = 0.62

(0.49–0.79, P<0.0001)

13.9 vs 11.0

HR = 0.78 (0.64–0.96, P = 0.0195)

Shepherd et al. [108] (second-line) Docetaxel vs

best supportive care

204 Time to progression

2.47 vs 1.56 (P <0.001)

7.0 vs 4.6 (P = 0.047)
Hanna et al. [109] Pemetrexed vs 571 Overall: Overall:
(second-line) docetaxel 2.9 vs 2.9 8.3 vs 7.9
(P = not significant) (P = not significant)
Squamous: Squamous:
2.3 vs 2.7 6.2 vs 7.4
HR = 1.40 (1.01–1.96, P = 0.046) HR = 1.56 (1.08–2.26, P = 0.018)
Non-squamous: Non-squamous:
3.1 vs 3.0 9.3 vs 8.0
HR = 0.82 (0.66–1.02, P = 0.076) HR = 0.78 (0.61–1.00, P = 0.048)
CheckMate057 [120] Nivolumab vs docetaxel 582 (non-squamous

histology only)

2.3 vs 4.2 12.2 vs 9.4
(second-line) HR = 0.92 (0.77–1.11, P = 0.3932) HR = 0.73
(0.59–0.89,
P = 0015)
CheckMate017 [119] (second-line) Nivolumab vs docetaxel 271

(squamous histology only)

3.5 vs 2.8

HR = 0.62 (0.47–0.81, P = 0.0004)

9.2 vs 6.0

HR = 0.59 (0.44–0.79, P = 0.00025)

NR, not reported.

Adapted with permission from Pallis AG et al., Chemotherapy of advanced non-small-cell lung cancer, Clinical Investigation, Volume 3, Issue 1, pp. 265–279, Copyright © 2013 Future Science.

No single regimen has clearly demonstrated superiority in unselected patients with advanced NSCLC. The largest trial comparing different platinum-based doublet regimens (cisplatin-paclitaxel, cisplatin-gemcitabine, cisplatin-docetaxel, carboplatin-paclitaxel) failed to demonstrate any difference in response or survival among the four arms [66]. Pemetrexed is preferred to gemcitabine in patients with non-squamous tumours based on a survival benefit demonstrated in a planned subgroup analysis of a randomized phase III first-line trial, whereas it was shown inferior in patients with tumours of squamous histology [79].

Поддерживающая терапия

Prolongation of the initial chemotherapy doublet from four to six cycles did not improve survival and resulted in substantial additional toxicity in a randomized phase III trial [80]. Prolongation of treatment beyond four to six cycles was associated with a statistically signifi ant improvement in progression-free survival (PFS), and a modest but significant improvement in survival in one meta-analysis. Prolongation of treatment, however, was also associated with a higher rate of adverse events and possible impairments of health-related quality of life [81]. Two further meta-analyses evaluating the effects of prolonged first-line third generation platinum doublet chemotherapy beyond four cycles could not demonstrate any improvement in OS [82, 83], establishing the standard of frontline 4 cycles of platinum-based chemotherapy [83].

In clinical practice, only 50–60% of patients receive second-line treatment, with rapid disease progression being the main reason for not administering subsequent therapies. In an attempt to improve the results of first-line combination therapy administered for a standard number of cycles, several maintenance strategies have been tested, either continuing one agent previously administered as first-line (continuation maintenance) or commencing an agent with a different mechanism of action (switch maintenance). Maintenance therapy is given without treatment-free period after the completion of first-line chemotherapy. Numerous randomized trials have demonstrated that maintenance treatment is associated with an improvement of PFS, as well as OS to a variable extent depending on defined strategy [84].

Docetaxel switch maintenance improves PFS with a trend for OS improvement after four cycles of carboplatin and gemcitabine, with no detrimental effect in quality of life [85]. Erlotinib switch maintenance therapy improved PFS in two randomized trials. OS was prolonged with erlotinib in the largest, adequately powered trial to detect such differences, but this benefit was restricted to patients with stable disease after completion of first-line chemotherapy. This benefit was also seen in the patient subgroup without activating mutation of the EGFR gene [86, 87]. These results could not be reproduced with gefitinib switch maintenance [88]. Continuation maintenance with gemcitabine was tested in three randomized clinical trials, with improvement in time-to-treatment failure (TTF) or PFS in two, without improvement in survival, potentially because of sample size [87, 89]. Pemetrexed, either as switch maintenance or continuation maintenance, improves both PFS and OS, with no significant impact on quality of life [90, 91]. Its use should be restricted to patients with non-squamous tumours [92].

To date, there is no definite clinical parameter or biomarker helping to identify patients at risk of rapid progression that would potentially benefit more from a maintenance strategy. In addition, there is very limited comparative evidence among the different maintenance options, and maintenance decisions are currently often left to the physician’s clinical judgment and subject to discussion with the patient.

Maintenance therapy should not be offered to patients with a performance status of 2 or greater or with persistent chemotherapy-induced toxicity. Furthermore, despite the low rate of grade 3 or 4 toxicities during maintenance treatment, the prolonged exposure of patients to grade 1 or 2 toxicities may be of significant concern.

Пожилые пациенты и пациенты с плохим общим состоянием

Age and comorbidity may limit tolerance to chemotherapy. Single-agent chemotherapy offers a survival benefit compared to best supportive care in elderly NSCLC patients, where gemcitabine was shown similar activity to vinorelbine [93, 94]. The combination of monthly carboplatin with weekly paclitaxel in patients aged 70–89 years with PS 0–2 offers an advantage in PFS and survival over single-agent treatment with either vinorelbine or gemcitabine [95]. In patients with performance status of 2, combination therapy of carboplatin and pemetrexed offers a significant survival advantage over pemetrexed alone [96].

Добавление таргетирующих агентов к химиотерапии в терапии первой линии

Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), improved survival when administered concurrently with paclitaxel and carboplatin and continued until disease progression in patients with non-squamous NSCLC [97]. Another large placebo-controlled randomized trial with two doses of bevacizumab combined with gemcitabine-cisplatin failed to demonstrate survival advantage [98], although PFS prolongation was observed. A meta-analysis of four randomized trials demonstrated a clinically marginal survival improvement with bevacizumab (HR = 0.90, P = 0.03) as compared with chemotherapy alone [99]. Bevacizumab treatment is associated with a higher risk of thrombosis, hypertension, bleeding, proteinuria, and pulmonary haemorrhage [100]. When considering bevacizumab therapy, an individualized risk-benefit assessment should be undertaken in all patients. Bevacizumab is contraindicated in patients with squamous NSCLC or history of haemoptysis, but can be used in patients with previously treated brain metastases and in patients with full anticoagulation [101].

Cetuximab, a monoclonal antibody against EGFR, has been tested in two fi st-line phase III trials in combination with cisplatin-vinorelbine or cisplatin-taxane [102, 103]. A modest survival prolongation was observed in the fi st trial only. EGFR protein expression intensity was retrospectively identified as a potential predictive biomarker of cetuximab effi acy. Due to confl  ting results, cetuximab is no longer being developed in the indication of NSCLC. Necitumumab, another monoclonal antibody against EGFR, has been tested in two parallel fi st-line phase III trials in combinations with platinum-based chemotherapy. The fi st trial, comparing necitumumab plus pemetrexed and cisplatin with pemetrexed and cisplatin alone in patients with previously untreated non-squamous NSCLC was stopped early based on the absence of any difference in overall survival between treatment groups [104]. The second trial, focusing on squamous NSCLC patients using a gemcitabine and cisplatin chemotherapy backbone demonstrated a modest improvement in survival, with no improvement of the objective response rate or median PFS [105].

Лечение второй и последующих линий

All patients inevitably develop progressive disease after first-line chemotherapy. Second-line treatment with either chemotherapy or EGFR TKI may provide symptom palliation and prolong survival. Combination regimens have failed to show any survival benefit over single-agent regimens in one meta-analysis [106]. Erlotinib was shown to improve survival in unselected second-line or third-line NSCLC patients not eligible for further chemotherapy with tumours of all histologies [107]. Docetaxel significantly improved survival compared with best supportive care [108]. Pemetrexed showed similar RR and survival in a comparison with docetaxel, with less toxicity [109]. Erlotinib was also shown to be of similar effi acy compared with docetaxel or pemetrexed in unselected patients refractory to fi st-line platinum-based chemotherapy [110]. Gefitinib was proven non-inferior to docetaxel [111]. Also in the second-line setting, afatinib, an irreversible second-generation pan-Her TKI inhibiting EGFR, HER2 and HER4, has demonstrated a modest median OS benefit when compared to erlotinib in patients with squamous cell carcinoma of the lung [112]. Median PFS, disease control rate, and global health status/quality of life were also improved, while toxicity was higher. It should be noted, however, that when NSCLC patients are selected by EGFR gene mutation status, those with tumours characterized by a wild-type EGFR demonstrate a better survival when treated with second-line docetaxel as compared to erlotinib [113–115] as shown by a randomized phase III trial and at least two meta-analyses. Thus, assessment of EGFR mutation status in tumours is mandatory for clinical decisions favouring EGFR TKIs or chemotherapy. In case of EGFR mutation-positive or negative NSCLC, EGFR TKIs are not considered an appropriate second-line treatment for patients considered fit to receive chemotherapy.

The addition of anti-angiogenic agents to docetaxel has been shown to improve its efficacy. Ramucirumab, a human monoclonal antibody against the extracellular domain of vascular endothelial growth factor receptor 2 (VEGFR-2), showed improved response rate, median PFS, and OS compared to docetaxel alone, in patients with both squamous and non-squamous histology [116]. The addition of nintedanib, an oral angiokinase inhibitor to VEGFR1-3, fibroblast growth factor receptors (FGFR) 1-3, and platelet-derived growth factor receptors (PDGFR) alpha and β, showed a benefit in median PFS compared to docetaxel in patients with NSCLC, and a benefit in median OS compared to docetaxel but only restricted to the patients with adenocarcinoma, an effect also shown to be most prominent in those patients who had progressed within nine months after initiation of first-line therapy in a retrospective subgroup analysis [117].

Additional anticancer agents, including gemcitabine, paclitaxel, vinorelbine, topotecan, and irinotecan, show some activity in chemotherapy-pretreated patients, but have not been adequately evaluated in randomized clinical trials and thus are not routinely recommended. Efficacy of all agents in this setting is generally poor, with response rates below 10% and median survival around six months. Significant improvements in overall quality of life with second-line treatment are infrequent. Quality of life can nevertheless be maintained using single-agent docetaxel or pemetrexed [109, 118].

Recent data have shown that docetaxel second-line chemotherapy as a standard of care after platinum-based doublet chemotherapy has been supplanted by immunotherapeutics. Two phase III trials of nivolumab, a fully human programmed-death (PD)-1 immune checkpoint inhibitor, versus docetaxel conducted in squamous and non-squamous histologies, respectively, have demonstrated a superiority in median OS, median PFS, RR, and toxicity for nivolumab, with a hazard ratio for death of 0.57 in patients with squamous NSCLC, and 0.73 for non-squamous histology, while being considerably less toxic than docetaxel [119, 120]. Other promising checkpoint inhibitors are in late-phase clinical development and predictive factors for the benefit from these therapies, such as immunohistochemical evaluation of PDL-1 ligand in the tumour and stroma, are currently being evaluated. The exact sequence of immune checkpoint inhibitors and chemotherapy will be refined over the next years, evaluating first-line immunotherapy strategies as well as combination with chemotherapy or targeted therapies.

Patients progressing after second-line chemotherapy are sometimes considered for further chemotherapy therapy in clinical practice, depending on performance status and toxicities from previous treatments. However, the evidence favouring efficacy of third-line therapy is lacking, with the exception of erlotinib in patients not eligible for further chemotherapy [107]. Clinical trials should strongly be considered in this setting, particularly with designs based on selection of patients based on molecular predictive assays.

Лечение пациентов с немелкоклеточной карциномой легкого с EGFR мутацией или ALK перестройкой

EGFR мутации

Sensitizing mutations in the EGFR sequence coding for tyrosine kinase are observed in approximately 15% of lung adenocarcinomas in Caucasian populations. These aberrations occur more frequently in patients from the Far East, never or light smokers and females. Testing for EGFR mutations is not recommended in patients with a confident diagnosis of squamous cell carcinoma, except in never/former light smokers (<15 packs per year). The presence of an EGFR activating mutation confers a more favourable prognosis and is strongly predictive of sensitivity to EGFR TKI therapy. Several randomized studies confi med the value of fi st-line reversible EGFR TKIs (gefitinib and erlotinib) as compared to chemotherapy [121–126]. Selected large trials addressing the role of EGFR tyrosine kinase inhibitors vs chemotherapy in patients with tumours harbouring EGFR mutations are summarized in Table 46.5. All but one of these phase III trials were conducted in Asian populations. Cross-study comparisons suggest that, although the incidence of EGFR mutations is lower in Caucasian populations, the response rates and PFS are similar in Asian patients with EGFR mutations. All these studies consistently report superior response rates (58.1 to 84.6% vs 14.9 to 47.3%) and PFS (9.7 to 13.7 months vs 4.6 to 6.7 months) to EGFR TKI therapy as compared to standard chemotherapy, with more favourable toxicity profiles and improved quality of life. None of these studies could demonstrate an improvement of survival (median ranging from 19.3 to 30.1 months), probably because of intensive crossover from chemotherapy to EGFR TKI at disease progression in the control arms. The second generation irreversible EGFR TKI afatinib also showed a significant PFS benefit compared with cisplatin-pemetrexed, at the expense of higher incidence of skin rash, diarrhoea, and mucositis [127, 128]. No adequately powered trial has directly compared gefitinib, erlotinib, and afatinib. In a pooled analysis of two trials comparing afatinib with cisplatin-based doublet chemotherapy, overall survival was significantly longer for patients with del 19-positive tumours in the afatinib group than in the chemotherapy group, while there was no significant difference by treatment group for patients with point mutation EGFR Leu858Arg in exon 21 positive tumours. As with first-generation reversible EGFR TKIs, response rates and median PFS were greatly improved in the afatinib group as compared with the chemotherapy groups, in both del 19-positive tumours and EGFR Leu858Arg-positive tumours [129]. The same observation about differential biology of del 19-positive tumours and EGFR Leu858Arg-positive tumours [129] when treated with EGFR TKI, in particular in terms of PFS, was confi med in a subsequent meta-analysis [130].

Таблица 46.5. Селективные клинические исследования, сравнивающие ингибитор EGFR тирозинкиназы первой линии с химиотерапией пациентов с EGFR активирующей мутацией

Study [ref] Author EGFR tyrosine kinase inhibitor Control arm Number of patients Tumour response rate Median progression-free survival [months] Hazard ratio (95% CI;

P-value)

Median survival [months] (95% CI) Hazard ratio (95% CI; P-value)
IPASS [121] Mok et al. Gefitinib Carboplatin/paclitaxel 261 71.2 vs 47.3 9.8 vs 6.4 HR = 0.48

(0.36–0.64, P < 0.001)

21.6 vs 21.9 HR = 1.00

(0.76–1.33, P = 0.99)

WJTOG 3405 [123] Mitsudomi et al. Gefitinib Cisplatin/docetaxel 172 62.1 vs 32.2 9.6 vs 6.6 HR = 0.52

(0.38–0.72, P < 0.0001)

35.5 vs 38.8 HR = 1.18 (0.77–1.83)
NEJ002 [124] Maemondo et al. Gefitinib Carboplatin/paclitaxel 228 73.7 vs 30.7 10.8 vs 5.4 HR = 0.32

(0.24–0.44, P < 0.001)

27.7 vs 26.6 HR = 1.04

(0.63–1.24, P = 0.31)

OPTIMAL [125] Zhou et al. Erlotinib Carboplatin/gemcitabine 154 83.0 vs 36.0 13.7 vs 4.6 HR = 0.16

(0.11–0.26, P < 0.0001)

22.7 vs 28.9 HR = 1.04 (0.69–1.58)
EURTAC [126] Rosell et al. Erlotinib Cisplatin or carboplatin/docetaxel

Or Cisplatin or carboplatin/

gemcitabine

173 58.1 vs 14.9 9.7 vs 5.2 HR = 0.37

(0.25–0.54, P < 0.0001)

19.3 vs 19.5 HR = 1.04 (0.65–1.68)
LUX-lung 3

[127]

Sequist et al. Afatinib Cisplatin/pemetrexed 345 56 vs 23 11.14 vs 6.90 HR = 0.58

P < 0.001

28.2 vs 28.2 HR = 0.88 (0.66–1.17)
LUX-Lung 6

[128]

Wu et al. Afatinib Cisplatin/gemcitabine 364 66.9 vs 28.0 11.0 vs 5.6 HR = 0.28 P < 0.0001 23.1 vs 23.5 HR = 0.93 (0.72–1.22)

NR, not reported.

Concurrent continuous administration of chemotherapy and EGFR TKI does not provide any response or survival advantage [131, 132]. EGFR tyrosine kinase inhibitors were also tested with pharmacodynamic separation, i.e., starting the EGFR inhibitor several days after cytotoxic agents and stopping before the next chemotherapy cycle (‘intercalated schedules’). A phase III study testing intercalated erlotinib with gemcitabine-cisplatin resulted in improved PFS and survival in the subset of patients with EGFR-mutated tumours, despite extensive crossover to erlotinib in the control arm [133]. Further studies with intercalated schedules in patients with EGFR mutation-positive NSCLC are needed before this treatment strategy is introduced into routine practice. Continuation of gefitinib beyond progression in combination with cisplatin and pemetrexed in patients with acquired resistance to gefitinib does not improve outcome [134], as shown in a phase III randomized trial. Central nervous system penetration of erlotinib or gefitinib is limited (approximately 1–5% of plasma levels), but are, however, sufficient to obtain responses similar to extracranial disease [135]. Despite initial activity of EGFR TKIs, all patients eventually develop acquired resistance. The most common mechanism of resistance is the EGFR T790M secondary mutation, which accounts for 50–60% of cases, and prevents gefitinib or erlotinib from binding to the ATP-binding pocket of EGFR protein. Second generation EGFR TKIs are effective in preclinical gefitiniband erlotinib-resistant EGFR T790M models, but their delivery in EGFR TKI resistant patients have shown modest activity to date in the clinic, with low response rates and side effects limiting the ability to administer doses that effectively inhibit T790M EGFR [136, 137]. Third-generation ‘mutant-selective’ irreversible EGFR TKIs specifically inhibit T790M and other activating EGFR mutations while sparing wild-type EGFR. Among these, mereletinib and rociletinib are in the late phase of their development [138, 139]. Other mechanisms of resistance include MET amplification, HER2 amplification, BRAF mutation, or histologic transformation to small-cell lung cancer [140].

ALK перестройки

Translocations involving the ALK (anaplastic lymphoma kinase) tyrosine kinase are present in approximately 2–4% of lung adenocarcinomas in Caucasian populations, more frequently in younger patients and light or never-smokers. Patients with tumours harbouring ALK rearrangement more often present with brain and liver metastases as well as pleural and pericardial effusions. The presence of an ALK rearrangement is strongly predictive of sensitivity to ALK inhibitor therapy. Crizotinib, an oral ALK, MET and ROS1 inhibitor, provides increased response rates and PFS compared to either pemetrexed or docetaxel monotherapy, respectively, in the second-line setting [141] (median of 7.7 vs 4.2 vs 2.6 months). Because of signifi ant crossover of patients from the chemotherapy arm at the time of progression, OS was not signifi antly different. In the fi st-line setting, crizotinib signifi antly improves response rate and PFS (median

10.9 vs 7.0 months) when compared to cisplatin or carboplatin plus pemetrexed, establishing crizotinib as the standard fi st-line treatment in this subgroup [142]. Crizotinib is generally well tolerated and is associated with gastrointestinal disturbance, visual changes, low testosterone levels, and elevated transaminases. Low penetration of crizotinib into the central nervous system might result in underexposure of brain metastases to the drug, leading to ‘pharmacodynamic resistance’, a phenomenon of exclusive progression in the brain while response in other tumour sites is maintained [143]. Several resistance mechanisms to crizotinib have been identified, including active ALK-dominant (resistance mutations and ALK copy number gain) and ALK non-dominant pathways (the outgrowth of clones containing a separate activated oncogene) [19]. Second-generation ALK inhibitors are more potent against ALK in vitro than crizotinib and can overcome selected ALK kinase domain mutations associated with resistance to crizotinib. Among these, ceritinib and alectinib are in the late phase of their development. Both drugs demonstrate activity against central nervous system disease [144], owing to their related better CNS penetration [145]. Ceritinib and alectinib have been approved in the setting of crizotinib resistance in some countries [146].

Other agents, including third generation ALK TKIs, are under development [147].

Лечение олигометастатической болезни

Stage IV NSCLC patients presenting with solitary metastases localized to brain, adrenals, or lung can be considered for treatment with curative intent after adequate staging workup has been conducted. Prognosis of patients with oligometastatic NSCLC is worse for synchronous metastases than for metachronous metastases. In the case of solitary brain metastasis, surgical resection, or stereotactic radiosurgery may be of benefit. The addition of whole brain radiotherapy (WBRT) after surgery or stereotactic radiotherapy was tested in a phase III trial in patients with one to three metastases from different primary sites, most commonly from NSCLC [148]. This study, conducted in 359 patients, demonstrated better local control after WBRT but no impact on survival. Five-year survival in patients in whom complete resection of metastases has been achieved ranges from approximately 10% to 30%. In the case of solitary adrenal metastasis, prolonged survival after resection of both primary tumour and adrenal has been suggested, with a five-year survival of 10–26% [149, 150]. There are no data regarding the role of adjuvant chemotherapy in patients who have undergone curative resection of a brain or adrenal metastasis, however most physicians use systemic treatment in this setting. A solitary pulmonary lesion in a different lobe, particularly in the absence of mediastinal lymph node involvement, should be considered as a synchronous second primary tumour and treated with curative intent. The survival of these patients is highly variable according to reported series, with five-year survival ranging from 0 to 50% according to patient selection criteria.

Лечение мелкоклеточной карциномы легкого и других нейроэндокринных опухолей

Мелкоклеточная карцинома легкого

Until recently, SCLC has been classified into two stage categories: limited and extensive disease. This practical classification, introduced by the Veterans Administration Lung Cancer Study Group, was used in most clinical trials conducted in SCLC that provided evidence for present standards of care. According to the current 7th edition of the AJCC TNM classification, limited disease corresponds to T1-T4 N0-N3 M0 whereas extensive disease corresponds to any T/any N, M1a or M1b stage categories.

Мелкоклеточная карцинома легкого ранней стадии (T1-T4 N0-N3 M0)

Prognosis of patients diagnosed with early stage SCLC is characterized by median survival of approximately 16–24 months and five-year survival probability of approximately 20%. Extensive evidence supports chemoradiotherapy as the standard of care in fit early stage patients who are candidates for this treatment. Historically, the introduction of chemotherapy improved very poor outcomes of these patients, some of whom had been previously treated with surgery. Subsequent addition of chest radiotherapy increased three-year survival probability by 5.4% according to the meta-analysis of several trials [151]. Further trials focused on optimization of chemotherapy, optimization of radiotherapy, and better integration of these treatment modalities.

A combination of four to six cycles of cisplatin-etoposide is recommended for treatment of patients with early stage SCLC [152].

Although similar results are achieved with carboplatin-etoposide [153], small number of patients with limited disease in the meta-analysis precludes definitive conclusions regarding equivalence of both schedules. Anthracycline-based schedules are inferior to platinum-based chemotherapy in patients with early-stage SCLC [154] and are more toxic when combined with radiotherapy, and are therefore not recommended. No progress has been observed with other agents or strategies tested to improve systemic treatment results of early SCLC.

Optimal timing of chemotherapy and radiotherapy has been studied extensively in the past. Data from clinical trials and several meta-analyses [155, 156] have yielded conflicting results, with some studies suggesting the benefit from early (starting with the first or second chemotherapy cycle) vs late radiotherapy, whereas other trials did not confirm this finding. When analysis was limited to trials with radiotherapy combined with platinum-etoposide, the benefit from early concurrent treatment was observed, particularly in trials in which dose intensity of chemotherapy was maintained despite early administration of radiotherapy. Another meta-analysis of four randomized trials with platinum-etoposide chemotherapy indicated that time of start of any treatment to end of radiotherapy (SER) of less than 30 days was associated with significantly better five-year survival probabilities at the expense of higher severe esophagitis rates [157]. Thus, combined chemotherapy with early radiotherapy (starting with the first or second cycle) should be considered in fit patients with early stage SCLC. In practice, there are patients who are not candidates for early chemoradiation due to comorbidities or due to large tumour volume affecting planned dose-volume parameters to the extent precluding definitive treatment. In such patients, late or sequential radiotherapy should be considered. Post-chemotherapy target volumes for primary tumour are sufficient in treatment planning, but all initially affected lymph node stations should be included in the radiotherapy field.

Optimal chest radiotherapy dose and fractionation has also been studied extensively. Most radiotherapy departments recommend either a hyperfractionated accelerated schedule of 45 Gy delivered twice daily or a conventionally fractionated or slightly hypofractionated schedule of 54–66 Gy delivered every day. Dose and schedule of concurrent radiochemotherapy in SCLC is often considered individually taking into account planning target volumes and expected toxicity based on dose distribution in organs at risk, particularly lung and oesophagus. The rationale to use accelerated radiotherapy schedules stems from radiobiological data of increased SCLC radiosensitivity to low radiation doses. In the pivotal clinical trial that addressed the issue of accelerated hyperfractionation [158], long-term survival was significantly increased from 16% (standard arm, 45 Gy in 25 fractions once daily) to 26% (experimental arm, 45 in 30 fractions twice daily) at the expense of higher severe esophagitis rates (11% and 27%, respectively). Despite this evidence, recommended also in current European guidelines for management of SCLC [152], some radiation oncologists still use conventionally fractionated doses of 60 Gy or more arguing that radiation dose in the standard arm of the above-mentioned Intergroup study is inadequately low, twice daily radiotherapy is logistically difficult and associated with clinically problematic oesophageal toxicity. Two large clinical trials are ongoing to address the optimal radiotherapy dose and schedule in SCLC (CONVERT trial conducted in Europe and Canada, comparing 45 Gy in 30 fractions and 70 Gy in 35 fractions and the CALGB 30610/RTOG0538 trial conducted in the United States assessing three different fractionation schedules). Results of these trials should provide further evidence to guide clinical practice.

Prophylactic cranial irradiation (PCI) should be given to all patients who have responded to initial treatment. The main goal of this therapy is to reduce the incidence of brain metastases by approximately 50% and to increase long-term survival by approximately 5%, as evidenced by meta-analysis of individual data from seven randomized trials that included mostly patients with limited disease SCLC [159]. The optimal dose of PCI was analysed in the phase III Intergroup trial led by French investigators, in with patients were randomly allocated to 25 Gy or 36 Gy [160]. The incidence of brain metastases at two years, the primary study endpoint, was not significantly different between study arms (29% and 23%, respectively, P = 0.18). Worse survival was observed in the high PCI dose arm due to a higher number of cancer-related deaths (HR = 1.20, P = 0.05). Minor neurological decline in time was noted across both arms of the trial with no difference between radiation doses [161]. While this study established 25 Gy in 10 fractions as a standard dose for PCI in patients with SCLC, some centres continue to use the dose of 30 Gy in 15 fractions, which was not compared in clinical trials. The advantages of PCI may be offset by increased neurocognitive deficits in elderly patients with pre-existing dementia, mandating careful consideration of its use in this patient category.

The value of surgery is debated in very early SCLC with no nodal involvement. In this rare patient category, no comparative evidence-based data exist to guide management. Results of surgical treatment followed by adjuvant chemotherapy are relatively good with long-term survival in the order of 30–50% [162], prompting many physicians to recommend this strategy in highly-selected patients. If this approach is taken, prophylactic cranial irradiation should be also routinely performed and chest radiotherapy should be considered in patients with incomplete resections [152].

Метастатическая мелкоклеточная карцинома легкого (любой T, любой N, M1a или M1b)

The first proof of benefit of cytotoxic agents in SCLC was demonstrated in the early 1970s when studies exploring cyclophosphamide demonstrated significant survival prolongation compared to best supportive care. Subsequently, a number of other agents and combination therapies were tested with anthracyclines, etoposide, and platinum compounds selected as the most active in this disease. Combination of cyclophosphamide, doxorubicin, and vincristine (CAV), cyclophosphamide, doxorubicin, and etoposide (CAE), or cyclophosphamide, doxorubicin, vincristine, and etoposide (CAVE) were shown to have similar efficacy to cisplatin-etoposide in patients with extensive SCLC, whereas cisplatin-etoposide was associated with better outcome and was less toxic when combined with thoracic radiotherapy in patients with limited SCLC. Platinum-etoposide is also associated with less myelosuppression as compared to anthracycline-based chemotherapy. The optimal duration of first-line chemotherapy was established to be four to six cycles. Several other strategies were tested in the last two decades in phase II or phase III clinical trials: alternating treatment with different schedules, maintenance treatment, chemotherapy dose intensification with or without hematopoietic growth factor support, addition of other cytotoxic agent to platinum-etoposide, use of targeted therapies, or immunotherapy. These strategies failed to improve clinically meaningful patient outcomes. Several clinical trials comparing cisplatin and carboplatin were summarized in a meta-analysis from individual data of 663 patients [153]. Median survival of patients treated with cisplatin-based chemotherapy was 9.6 months as compared to 9.4 months for carboplatin (HR = 1.08, P = 0.37). Use of carboplatin was associated with more haematological toxicities, whereas use of cisplatin was linked to higher likelihood of nausea/vomiting, peripheral neuropathy, and renal impairment. In the last decade, a set of studies was conducted with campthotecin derivatives (topoisomerase I inhibitors: irinotecan and topotecan) and amrubicin, an anthracycline with favorable cardiac toxicity profile and high topoisomerase II inhibition potency. A phase II clinical trial conducted by the Japanese Clinical Oncology Group evaluated cisplatin-irinotecan combination versus cisplatin-etoposide as front-line therapy in patients with metastatic SCLC [163]. The trial was closed after interim analysis of 154 patients showed a significantly superior survival favouring irinotecan (median survival of 12.8 months vs 9.4 months, P = 0.002). Phase III trials with irinotecan [164–167] or topotecan [168] conducted in the United States or Europe have not confirmed the superiority of campthotecins over platinum-etoposide, except for one trial in which relatively poor outcome of patients in a control group treated with carboplatin and oral etoposide was reported [165]. Amrubicin-cisplatin has shown similar efficacy to cisplatin-etoposide in one phase III first-line trial in metastatic SCLC [169]. In summary, four to six cycles of cisplatin-etoposide or carboplatin-etoposide combination are recommended in metastatic SCLC. In patients with SCLC who have contraindications to platinum compounds, anthracycline-based chemotherapy (CAE or CAV) should be considered as a reasonable alternative.

Reported response rates in patients with metastatic SCLC to first-line chemotherapy are in the order of 50–70%, median progression-free survival is approximately five months and OS is approximately 9–12 months. In patients who relapse, options for systemic treatment are limited and depend primarily on duration of response to first-line therapy, patient performance status, age, comorbidities, and toxicities from previous chemotherapy. Patients who respond to first-line chemotherapy and progress within three months of last chemotherapy administration are categorized as ‘refractory’ whereas those who have a longer relapse-free interval are categorized as ‘sensitive’. In patients with refractory disease, oral topotecan, intravenous topotecan, anthracycline-based chemotherapy, or best supportive care should be considered. In this category, treatment outcome is poor with response rates of approximately 5–20%. Patients with sensitive disease should be treated with single-agent topotecan, anthracycline-based chemotherapy, or re-induction with platinum-etoposide, particularly if relapse-free period exceeds six months. Reported response rates in this category are typically between 20–40%. In patients who received anthracycline-based chemotherapy as front-line treatment, subsequent therapy with platinum-etoposide should be considered.

Prophylactic cranial irradiation was investigated in metastatic SCLC patients who have responded to first-line chemotherapy in a phase III clinical trial that aimed to demonstrate the reduction of proportion of patients who experience clinical progression in the brain. The trial met its primary endpoint, showing that PCI reduces the risk of brain metastases from 40.4% in the control arm to 14.6% in experimental arm at one year. This trial also showed that the use of PCI is associated with survival benefit (median of 6.7 vs 5.4 months, respectively; HR = 0.68, P = 0.003). Based on the above study, PCI is recommended in metastatic SCLC patients who had a response to initial chemotherapy. Treatment should start within five weeks after the last chemotherapy cycle. The dose of 25 Gy in 10 fractions is most commonly used.

Карциноидные опухоли и крупноклеточная нейроэндокринная карцинома

The spectrum of neuroendocrine malignancies includes typical carcinoids (fewer than two mitoses per 2 mm2 or ten high power fields), atypical carcinoids (more than two mitoses per 2 mm2), large cell neuroendocrine carcinoma (LCNEC), and SCLC discussed above. Two former entities are low and intermediate grade whereas the two latter entities are high-grade neuroendocrine tumours. These two groups share neuroendocrine differentiation markers but have distinct molecular profiles and very different biological and clinical characteristics. Carcinoid syndrome, associated with serotonin and kallikrein secretion by the tumour, is manifested by flushing, diarrhoea, wheezing, and heart failure. Syndrome occurs in up to 3% of patients and is usually associated with a high tumour burden, and typically with liver metastases. Somatostatin receptors are present in the majority of neuroendocrine tumours and may be visualized by somatostatin scintigraphy (Octreoscan™) and indium-111 or gallium-68 radiolabelled PET tracers, used for the purpose of staging. Staging of carcinoids and LCNEC is performed according to current TNM classification. Due to low incidence, comparative evidence for management of carcinoids and LCNEC does not exist and most data are derived from single-arm trials or comparative trials in which pulmonary neuroendocrine tumours usually represent a minor proportion of patients.

Pulmonary carcinoids belong to the group of foregut neuroendocrine tumours, constitute up to 3% of lung malignancies and typically occur in the main bronchi. Peripheral carcinoids are observed in about 30% of cases. Ten-year survival probabilities for patients with typical and atypical carcinoids are approximately 90% and 50%, respectively. Distant metastases occur most commonly in the lungs, liver, and bones. Centrally located stage I and II carcinoids should be managed with lung parenchyma-sparing surgery and mediastinal lymph node dissection or sampling. Surgical margins may be minimal to avoid extensive resections. Atypical carcinoids are more likely to occur as peripheral lesions, hence a lobectomy is often considered in a patient with stage I or II disease and adequate pulmonary reserve, although limited resections may also be an option. Significant controversy exists regarding the optimal management of carcinoids with mediastinal lymph node involvement which is sometimes observed in the case of atypical tumours. In this setting, most physicians recommend a combined modality approach with aggressive surgery if technically feasible. Adjuvant chemotherapy or radiotherapy is not indicated for typical carcinoids and atypical carcinoids with no nodal involvement. Adjuvant chemotherapy is controversial in patients with atypical carcinoids and involved lymph nodes; prognosis of these patients is considerably worse, but there is no evidence of benefit from adjuvant treatment.

Several cytotoxic agents are used in the management of metastatic carcinoid tumours. These agents include cisplatin, carboplatin, etoposide, streptozocin, doxorubicin, and 5-fluorouracil. The response rates to platinum-etoposide or streptozocin-based regimens depends on tumour grade and is typically in the range of 10% for typical carcinoids and 20–50% for atypical carcinoids, with no clear evidence favouring any particular regimen. Somatostatin analogues, such as octreotide acetate long-acting repeatable (LAR) formulation, provide benefit to the majority of patients with hormone-related symptoms. Objective tumour responses to somatostatin analogues are infrequent (<10%), hence the direct anti-tumour effect of these agents have been debated. The PROMID trial, conducted in 85 patients with functionally active and inactive well-differentiated metastatic mid-gut neuroendocrine tumours, showed prolongation of time-to-progression in patients treated with long-acting octreotide as compared to placebo (median of

14.3 vs 6 months, HR = 0.34, P = 0.00072) [170]. Results of this study have been extrapolated to bronchiopulmonary carcinoids, although no clear evidence exists regarding survival benefit from the use of these agents. Radionuclide therapy with radiolabelled somatostatin analogues have been developed and tested in patients with positive diagnostic octreotide scintigraphy. In a phase II study, 90 patients with various carcinoid tumours refractory to octreotide therapy, received three doses of 90Y-edotreotide every six weeks. Objective responses were observed in 4% of patients, disease control was noted in 74% of patients, and median progression-free and overall survival was 16.3 and 26.9 months, respectively [171].

Recent clinical studies have demonstrated prolongation of progression-free survival in patients with pancreatic neuroendocrine tumours when treated with octreotide LAR combined with everolimus (mammalian target of rapamycin, mTOR inhibitor) or with sunitinib [172, 173]. The impact of these agents on outcomes of metastatic lung carcinoid patients is unknown.

Diagnosis of LCNEC is difficult, particularly in small specimens. LCNEC is an aggressive malignancy, most often diagnosed in locally advanced or metastatic stage, with clinical behaviour and spectrum of molecular aberrations similar to SCLC. The optimal chemotherapy has not been established in comparative trials. A retrospective analysis of patients with pure pulmonary LCNES suggests that platinum-etoposide is more effective than chemotherapy schedules typically used in NSCLC, such as cisplatin-gemcitabine or cisplatin-paclitaxel [174]. A prospective phase II trial exploring the efficacy of platinum-etoposide in 42 LCNEC advanced patients reported median progressionfree and overall survival of 5.2 and 7.7 months, respectively. Due to poor survival after surgery alone in stage I LCNEC, adjuvant chemotherapy is suggested similarly to SCLC.

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