Box 9.1 shows a classification of lung tumours, which is based on light microscopic assessment of patterns of differentiation. The most important distinction is between small cell carcinoma (SCLC: 15–25% of lung cancers) and other carcinomas, collectively called non-small cell carcinoma (NSCLC). These subgroups behave differently in their presentation, natural history and response to treatment.

Small cell carcinoma (SCLC)

SCLC is a highly malignant neuroendocrine tumour and typically presents as large central masses with atelectasis and extensive mediastinal lymphadenopathy. Two-thirds of the patients have detectable metastases at diagnosis and there is a high risk of brain metastases. Microscopically these tumours consist of small round cells with round or oval nuclei and nuclei and scant cytoplasm. Immunohistochemically these stain for cytokeratin as well as neuroendocrine markers (e.g. neuron specific enolase).

Non-small cell lung carcinoma (NSCLC)

NSCLC consist of the following types:

• Squamous cell carcinoma – which accounts for 30% of lung cancer, presents with large central lesions with associated atelectasis, pneumonitis and hilar and mediastinal lymphadenopathy. Cavitation is seen in up to 10% of cases. Microscopically these tumours show presence of keratin production and/or intercellular bridges.

• Adenocarcinoma (30–35%) – the proportion of adenocarcinoma has been increasing over time with a relative decrease in squamous cell and small cell carcinomas, and this trend is expected to continue. Adenocarcinoma usually presents as small peripheral lesions with a high propensity for nodal and distant spread. A variant of adenocarcinoma called bronchoalveolar carcinoma grows diffusely and has a characteristic appearance on chest X-ray mimicking slowly progressive or non-resolving ‘pneumonia’. Histological diagnosis is based on presence of neoplastic gland formation or intracytoplasmic mucin. Immunohistochemical staining with TTF-1 (thyroid transcription factor-1 which is expressed by lung adenocarcinoma and thyroid cancer) helps to distinguish metastastic adenocarcinoma (TTF-1 negative) from lung carcinoma.

• Large cell carcinoma (10–20%) tends to be a relatively large peripheral lesion and has high propensity for regional lymph node and distant metastasis. Microscopically this tumour is diagnosed by exclusion of all other types of lung cancer.

Other neuroendocrine tumours

These tumours have immunohistochemical (e.g. chromogranin) or electron microscopic (neurosecretory granules) evidence of neuroendocrine differentiation. They represent 2% of lung tumours and have heterogeneous behaviour.

• Typical carcinoid can occur centrally or peripherally, are not linked to smoking and have an excellent prognosis. Microscopically these tumours are composed of polygonal cells arranged in distinct organoid, trabecular or insular growth pattern. There will be <2 mitotic figures per 10 HPF and no necrosis.

• Atypical carcinoid shows morphological features of carcinoid with 2–10 mitotic figures per 10 HPF and/or necrosis. These are thought to be intermediate in behaviour between typical carcinoid and SCLC. There is no evidence that there is progression from typical carcinoid to atypical carcinoid and SCLC.

• Large cell neuroendocrine carcinoma has a worse prognosis than atypical carcinoid. These tumours have features of neuroendocrine tumour but do not meet the criteria of carcinoid, atypical carcinoid or small cell carcinoma. There will be prominent necrosis and more than 10 mitotic figures per 10 HPF.

Presentation

More than 90% of patients are symptomatic at presentation of which approximately 30% are due to tumour, 30% are due to non-specific systemic symptoms (anorexia, weight loss or fatigue) and 30% due to metastatic disease. Five percent of patients are asymptomatic and are detected incidentally.

Respiratory symptoms

Cough is the most common presenting symptom (70%), followed by dyspnoea (60%), chest pain/discomfort (50%) and haemoptysis (41%).

Other symptoms

Symptoms due to compression of recurrent laryngeal nerve (hoarse voice), phrenic nerve (breathlessness), brachial plexus (shoulder pain and/or arm pain, sensory changes and muscle wasting in the distribution of C8 and T1–2 nerves) and sympathetic plexus (Horner’s syndrome) can occur. Four percent of lung cancer patients present with superior venacaval obstruction (SVCO) and is most common with small cell lung cancer. Pleuritic chest pain and pleural effusion occurs in pleural involvement. Pericardium involvement can present with pericardial effusion and rarely, tamponade. Rarely, dysphagia due to massive nodal disease compressing the oesophagus can occur.

Bone pain is the presenting symptom in up to 25% patients. Liver involvement usually leads to pain if there is massive metastasis. Clinical adrenal insufficiency is rare. Brain metastases at diagnosis occur in up to 10% and present with features of raised intracranial tension, focal neurologic deficits, fits and mental and personality changes.

Paraneoplastic syndromes occur in up to 10% of patients. Box 9.2 lists the paraneoplastic syndromes. SCLC is the most common type associated with paraneoplastic neurologic syndromes. Hypercalcaemia either due to excess parathyroid hormone (PTH) or PTH-related peptides is common in squamous cell carcinomas (15%). Hyponatremia occurs in up to 10% of patients, which is either due to syndrome of inappropriate secretion of ADH (SIADH) or to atrial natriuretic factor. SIADH is commonly associated with SCLC.

Box 9.2
Paraneoplastic manifestations of lung cancer

Endocrine

Syndrome of inappropriate ADH secretion (SIADH)¹

Humoral hypercalcaemia of malignancy ²

Ectopic Cushing’s syndrome ¹^,³

Ectopic hCG syndrome ⁴

Growth hormone excess ³

Cardiovascular

Thromboplebitis ²

Arterial thrombosis

Marantic endocarditis

Haematological

Haemolytic anaemia

Red cell aplasia

Thrombocytosis

Others

Nephrotic syndrome

Hypouricaemia

Signs

A normal physical examination does not exclude lung cancer.

General: cachexia, finger clubbing, anaemia, enlarged supraclavicular lymph node, features of SVCO and Horner’s syndrome (in upper lobe tumours).

Chest: reduction of breath sounds over a lobe, signs of lobar collapse, inspiratory crackles over a lobe, unilateral wheeze, features of pleural effusion, rib tenderness.

Other systems: bone tenderness, hepatomegaly, features of brain metastasis, peripheral neuropathy and proximal myopathy.

Investigations and staging (Figure 9.1)

Evaluation of a patient with suspected lung cancer is to:

• establish histologic type

• define extent of disease (staging)

• assess fitness to undergo the best appropriate treatment.

Figure 9.1 Evaluation of lung cancer.

Imaging

Chest X-ray (Figure 9.2A) may show lung lesion with or without lymphadenopathy. There can be associated lung collapse, pleural effusion, synchronous nodules or pericardial effusion. Bone metastases or bony destruction due to direct invasion can also been seen.

Figure 9.2 Imaging in lung cancer.

Contrast enhanced CT scan of chest, including upper abdomen (3–10% patients show asymptomatic liver and/or adrenal metastasis – Figure 9.2B&C) should be performed prior to further diagnostic investigations including bronchoscopy.

Lymph nodes of >1 cm in short axis diameter, a central low intensity suggesting necrosis and rounding of the contour of a hilar node where it meets the lung margin suggest malignant lymph nodes. CT is not reliable in assessing lymphadenopathy, to distinguish T3 from T4 disease and in demonstrating chest wall invasion, which all are important in making treatment decision.

CT scan is useful in assessing resectability. Encasement of proximal pulmonary arteries/veins, gross mediastinal involvement by tumour, widespread mediastinal lymphadenopathy and distant metastasis on CT scan suggest an unresectable tumour (96% accuracy). Tumour invasion of central pulmonary artery and vein, involvement of main stem bronchus and tumour extension across the major fissure (anywhere on the left side, above the minor fissure on right), all suggest the need for pneumonectomy for complete resection.

CT scan of brain is done if there is clinical suspicion of brain metastasis or patient is planned to undergo curative treatment.

Bone scan is indicated if there is bone pain or isolated raised alkaline phosphatase.

Tissue diagnosis

Flexible bronchoscopic biopsy can be obtained in 60–70% of lung cancers (central tumours). Sampling using multiple techniques (biopsy, brushings and washings) gives the highest diagnostic yield (sensitivity of 83–88%).

CT guided percutaneous needle aspiration/biopsy – is useful in peripheral tumours. Core biopsies improve the sensitivity compared with aspirates. Complications include bleeding and pneumothorax.

Fine needle aspiration is suitable for sampling lymph nodes, skin nodules and liver and adrenal metastases. Pleural effusion requires aspiration, biochemical analysis and cytology together with multiple pleural biopsies.

Sputum cytology has wide variation in sensitivity (10–97%) and should be reserved for patients with central tumours who are unable to tolerate or unwilling to undergo bronchoscopy or other invasive procedures.

Staging

Stage determines prognosis and guides treatment. TNM staging of lung cancer is given in Box 9.3. Small cell lung cancer can also be staged using a simple staging classification (Box 9.4). SCLC can be classified as TNM staging or using the simplied.

Box 9.3
Staging of non-small cell lung cancer

Stage Ia

T1N0	Tumour ≤3 cm diameter

Stage Ib

T2aN0M0	Tumour >3 cm or ≤5 cm OR
	Tumour of ≤5 cm with involvement of visceral pleura, main bronchus ≥2 cm distal to the carina or partial atelectasis

Stage IIA

T2bN0M0	Tumour >5 cm or ≤7 cm
T1-T2aN1M0	Metastasis in ipsilateral hilar or peribronchinal nodes

Stage IIB

T2bN1M0
T3N0M0	Tumour of >7 cm OR
	Tumour invading chestwall, diaphragm, phrenic nerves, mediastinal pleura or parietal pericardium OR
	Tumour <2 cm from carina, atelectasis of entire lung or nodule in the same lobe

Stage IIIA

T4N0-1M0	Tumour invading mediastinal structures or nodule in different ipsilateral lobe
T1-3N2M0	Metastases in ipsilateral mediastinal and/or subcarinal nodes

Stage IIIB

T4N2M0
anyT N3M0	Metastases in contralateral hilar or mediastinal nodes
anyT N3M0	Metastases in scalene or supraclavicular nodes

Stage IV

M1a	contralateral lung nodule/pleural nodule/malignant effusion distant metastasis
M2b

Box 9.4
Staging of small cell lung cancer

Limited stage (stage I-III)

Tumour confined to the hemithorax of origin, the mediastinum, and the supraclavicular nodes, that can be encompassed within a tolerable radiation therapy port.

Extensive stage (stage IV)

Tumor that is too widespread to be included within the definition of limited-stage disease above. Patients with distant metastases (M1) are always considered to have extensive stage disease.

Mediastinal staging in non-small cell lung cancer

Accurate distinction of stages II, IIIA and IIIB is important in deciding optimal surgical treatment in the potentially operable patients. Stage II disease is treated with lobectomy or pneumonectomy with mediastinal sampling or dissection. Stage IIIA disease may be treated with neoadjuvant chemotherapy followed radical surgery or radical chemoradiotherapy, whereas IIIB disease is unresectable. This necessitates both an accurate distinction of T3 from T4 tumours and an accurate staging of nodal status. A classification of mediastinal nodes is shown in Figure 9.3.

Figure 9.3 The classification of mediastinal nodes, patterns of nodal spread and method of choice of staging.

Methods of mediastinal staging

Positron emission tomogram (PET) (Figure 9.4) – PET is scan based on the principle of differential uptake of 2-[fluorine-18]-fluoro-2-deoxy-D-glucose (FDG) by cancer cells. FDG is metabolized at a higher rate by tumour cells than normal cells and the areas of increased activity can be detected by a scanner. FDG-PET has higher sensitivity (87% vs. 68%), specificity (91% vs. 61%) and accuracy (82% vs. 63%) at detecting mediastinal disease than CT scan. PET also has a high negative predictive value in exclusion of N2/N3 disease, which helps to omit further mediastinal staging in case of a negative PET. Overall, there is 20% improvement in accuracy of PET over CT for mediastinal staging of NSCLC.

Figure 9.4 PET scan in lung cancer.

PET also detects distant metastases. The incidence of extra thoracic metastases on PET which are not suspected by CT scan is 9 to 11%. CT false-positive adrenal nodules have been correctly identified as negative on FDG-PET.

One of the limitations of PET is false-positive ‘hot spots’ in the mediastinum due to inflammatory processes (in up to 13 to 17%). It is less accurate when the lesion is <1 cm and in tumours of low metabolic activity such as carcinoid and bronchoalvelolar carcinoma.

PET scan is recommended for all NSCLC patients being considered for radical treatment. Patients with no lymphadenopathy on CT scan but with PET scan positive nodal disease needed mediastinoscopy prior to definitive treatment as 50% of patients can have false positive PET scan.

MRI scan – has limited role in staging. This may be useful to evaluate vascular and vertebral body invasion and to assess integrity of brachial plexus in Pancoast’s tumour.

Endobronchial ultrasound (EBUS) – EBUS is able to penetrate up to 5 cm and can identify lymph nodes and vessels. It is helpful in visualizing paratracheal (stations 2 & 4) and peribronchial lymph nodes (see Figure 9.3) and enables EBUS guided transbronchial needle aspiration (Figure 9.5). Sonographic features of malignant lymph node are round shape, sharp margins and hypoechoic texture. The advantage of EUS over CT and PET is that it can characterize lymph nodes smaller than 1 cm. It can also determine the depth and extent of tumour invasion of tracheobronchial lesions and helps to define the relationships to the pulmonary vessels and the hilar structures. EBUS has been found to predict the lymph node staging correctly in 96% of cases, with a sensitivity of 95% and specificity of 100%.

Figure 9.5 Endobronchial ultrasound (A) and its use for FNA (B) of an enlarged lower paratracheal node (C&D).

Endo-oesophageal US (EUS) with fine needle aspiration is useful to assess sub-aortic (station 5), subcarinal (station 7), and paraoesophageal (station 8) lymph nodes as well as the upper retroperitoneum, which are not accessed by mediastinoscopy. It is envisaged that EUS-FNA and EBUS will not replace but will complement surgical techniques like mediastinoscopy.

Transbronchial needle aspiration (TBNA) – TBNA using a flexible fibre optic bronchoscope has a sensitivity of 78% and high specificity (approaching 100%) for identifying mediastinal metastases. However, the diagnostic yield is operator dependent.

Mediastinoscopy is generally regarded as the gold standard for preoperative mediastinal evaluation. CT scan is helpful in guiding selection of patients for mediastinoscopy prior to surgery. Cervical mediastinoscopy allows better access to contralateral lymph nodes. It is useful in evaluating paratracheal (2 & 4), scalene and inferior mediastinal nodes (7, 8 & 9). It is not useful in evaluating aortic nodes (5 & 6). Mortality rates from mediastinoscopy are negligible, but morbidity rates especially arrhythmias are reported to be 0.5–1%. It has to be borne in mind that up to 30% of patients with lung carcinoma who have a negative mediastinoscopy prove to have mediastinal nodal metastasis at surgery.

Video-assisted thoracoscopy (VATS) is useful to evaluate aortic (5 & 6), paraoesophageal (8) and pulmonary ligament nodes (9). It is also useful in assessing the pleural cavity and obtaining pleural biopsies.

Management of lung cancer

Patients presenting with symptoms suggestive of lung cancer need urgent evaluation (Figure 9.1) and referral to a team specializing in the management of lung cancer. Treatment depends on type of lung cancer (NSCLC vs. SCLC), stage, performance status, co-morbidities and cardiopulmonary reserve.

Non-small cell lung cancer (Figure 9.6)

Stage I–II

Patients presenting with stage I–II disease are generally treated with curative intent if performance status is good (0–1) and pulmonary function are adequate. The treatment options include:

• Surgery alone (if excision complete).

• Surgery followed by radiotherapy (in case of microscopic residual disease).

• Surgery followed by chemotherapy (in selected cases of IB & II).

• Radical radiotherapy (in patients who are unfit or unwilling for surgery).

Figure 9.6 Management of non-small cell lung cancer. *palliative chemotherapy is considered only in patients with good performance status (0-2).

Radical surgery

Surgery offers the best prospect of cure in stage I–II disease, but only 10–20% of patients are suitable for surgery. Surgery is aimed at complete resection of the tumour and its intrapulmonary lymphatics. Patients need careful preoperative evaluation as they are often frail and frequently have cardiopulmonary morbidity due to chronic smoking. Spirometry is required in all patients. If the FEV1 is less than 1.5 L for lobectomy and less than 2 L for pneumonectomy, full lung function tests are required. Table 9.1 shows minimal pulmonary function required for different curative treatments. All patients require an ECG and patients with murmurs should have echocardiogram. Patients with known ischaemic heart disease should have detailed cardiologic assessment.

Table 9.1 Minimal pulmonary function for curative treatment

A complete anatomical resection is achieved by one of the following procedures:

• Lobectomy is the most common procedure which carries a postoperative mortality of 2–4%.

• Pneumonectomy is indicated if the tumour invades hilar structures (e.g. main bronchi, main pulmonary artery) and has a higher mortality rate (6–8%).

• Wedge or segmental resection is useful in patients with peripheral tumours and impaired lung function but carries a high rate of local recurrence (3–5 times) and a lower survival (reduce survival by 5–10%).

• Bronchoplastic or ‘sleeve’ resection is designed to spare lung tissue as an alternative to pneumonectomy. This procedure is used to resect endobronchial lesions at or adjacent carina to preserve distal tissue.

Radical radiotherapy (Table 9.2)

Patients with medically inoperable stage I/II are treated with radical radiotherapy if lung function is adequate (Table 9.1). In the only randomized trial, radiotherapy was inferior to surgery (4-year survival 7% vs. 23%). After conventional radical radiotherapy (60 Gy in 30 fractions over 6 weeks), 2-year survival is about 20%. A UK MRC study showed that 2-year survival is better (20 vs. 29%) with continuous hyperfractionated accelerated radiotherapy (CHART). This radiotherapy regime consists of 54 Gy in 36 fractions over 12 continuous days giving three fractions per day with a minimum interval of 6 hours between each fraction.

Table 9.2 Radiotherapy in lung cancer

An evolving technique of stereotactic radiotherapy typically delivers high doses of radiotherapy in 3–5 fractions using precise method of tumour localization and radiation delivery. Early results suggest a 2-year local control of >90% in patients with stage I tumours with <5% significant toxicity.

Postoperative treatment

Radiotherapy

There is no proven role for postoperative radiotherapy after complete surgical resection of stage I–II lung cancer. There is some suggestion that routine radiotherapy in N0–N1 disease significantly decrease survival. Hence radiotherapy may be offered in incomplete resection and/or unexpected N2 disease (improve local control with no effect on survival) if performance status and residual lung function permits. However, further studies are needed to define the exact role of radiotherapy in the adjuvant chemotherapy era.

Chemotherapy (Box 9.5)

In randomized trials, there is no survival benefit with adjuvant chemotherapy for stage IA. In stage IB and II, an early meta-analysis showed a 5% overall survival benefit with postoperative cisplatin-based combination chemotherapy. This has been supported by several recent trials of cisplatin combinations. The NCIC JBR 10 and ANITA trials both used vinorelbine and cisplatin. 5-year overall survival in NCIC JBR 10 trial was increased from 54 to 69% in stage IB and II disease. In the ANITA trial overall survival was not significantly different in stage IB (62% vs. 63%) but was statistically significant in stage II (52% vs. 39%) resected NSCLC. More heterogeneous trials which have allowed a wider range of tumour stages, more variety in chemotherapy combinations within the trial and less standardized surgical eligibility have provided less obvious benefits in survival (ALPI and European BIG lung trial). The IALT trial did however show a benefit in survival and the trial was closed early when the planned interim analysis showed a significant impact on survival with a median follow-up of 56 months. In summary, fit patients with resected stage IB–II should therefore be offered four courses of a cisplatin combination chemotherapy within 12 weeks of surgery.

Box 9.5
Chemotherapy regimes in lung cancer

Small cell lung cancer

• Carboplatin (AUC 5–6) + etoposide – is the usual first line regime.

• CAV (cisplatin, adriamycin and vincristine).

• ACE (Adriamycin, cyclophosphamide and etoposide.

• CAV & ACE are not given with concurrent radiotherapy as adriamycin causes ‘radiation recall’.

• Oral topotecan.

Stage III

Stage IIIA (T1–3, N2 M0/T3 N1 M0)

Patients with stage IIIA comprise a complex and heterogeneous group with varied treatment outcome. The result of surgery alone is poor and the expected 5-year survival is between <10 and 40%; it is dependent on the extent of mediastinal nodal involvement.

The treatment of choice is radical chemoradiotherapy if good performance status (0–1). Patients with small volume N2 disease can be considered for surgery after neoadjuvant chemotherapy or chemoradiotherapy.

The treatment options are:

• Radical chemoradiotherapy (for T1–3N2 disease with PS 0-1).

• Surgery alone or with postoperative radiotherapy and/or chemotherapy (for unexpected N2 disease after resection).

• Neoadjuvant chemo-radiotherapy or chemotherapy followed by surgery (for T3 N1 and small volume N2 disease, both with PS 0–1).

• Radical radiotherapy (if chemotherapy contraindicated, radical RT feasible & PS 0–1).

• Palliative chemotherapy (not suitable for radical radiotherapy and PS 2 or less).

• Symptomatic treatment and palliative radiotherapy (PS 2 or more).

The IALT trial and meta-analysis showed at least a 5% survival advantage with adjuvant chemotherapy in resected stage IIIA disease. Similarly, the ANITA trial also showed statistically significant improved survival with adjuvant vinorelbine and cisplatin in completely resected stage IIIA disease (42% vs. 26%).

Stage IIIB (T4 any N, M0/ any T N3 M0) without malignant effusion

Treatment options are:

• Radical chemoradiotherapy (if PS 0–1 and disease can be radically irradiated).

• Neoadjuvant chemoradiotherapy or chemotherapy followed by surgery (selected group with good PS).

• Radical radiotherapy (small radically treatable disease, PS 0–1, chemotherapy contraindicated).

• Palliative chemotherapy (not suitable for radical treatment and PS not >2).

• Symptomatic and supportive care.

In young fit patients with stage IIIB disease due to involvement of adjacent structures, neoadjuvant chemotherapy or chemoradiotherapy can be used to downstage the tumour and aim for surgical resection. There is a trend towards increased survival at least in the first 2 years for these patients particularly when chemotherapy is given concurrently with radiotherapy. Trials have examined dose and scheduling and concluded that full dose chemotherapy concurrently with radiotherapy was most beneficial.

Stage IIIB with malignant effusion/stage IV

Patients with malignant effusions (IIIB) or metastatic disease (IV) are incurable and both carry a similar prognosis. The treatment aim is palliative with the intention of improving symptoms as much as disease control. Treatments will be greatly affected by patient fitness as these patients will often be frail and suffer several co-morbidities. Many trials have examined the role of chemotherapy versus best supportive care in this group. Overall chemotherapy has a response rate of 20–40% with a duration of 6 months and a median overall survival of less than 1 year. The survival benefit from chemotherapy is in the range of 6–8 weeks. Response rates for an individual reflected overall survival in a meta-analysis. Frequent assessment prior to chemotherapy with CXR is recommended to assess response.

Chemotherapy has been associated with symptomatic benefits such as reduced palliative radiotherapy requirements, reduced analgesia, weight stabilization and maintenance of performance status. Toxicity was frequently seen, worse with combination chemotherapy but quality of life studies showed that these were not perceived as worse compared with patients not on chemotherapy.

In general, chemotherapy has a greater benefit in fit patients of good performance status (WHO 0 or 1). In these patients combination chemotherapy (a platinum and other agent such as vinorelbine or gemcitabine) can be offered. A recent study has shown that a combination of cisplatin and pemetrexed improves overall survival in patients with locally advanced or metastatic adenocarcinoma (12.6 vs. 10.9 months) and large cell carcinoma (10.4 vs. 6.7 months) compared with cisplatin and gemcitabine. In the less fit or elderly single agent treatments, palliative radiotherapy, biological agents or appropriate trials can be considered.

Recently phase III studies have shown that maintenance treatment with pemetrexed and erlotinib are useful in patients who had not progressed after first line chemotherapy.

Palliative radiotherapy

A significant number of patients may need radiotherapy to palliate symptoms. There will be a subgroup of patients with large localized NCSLC which cannot be encompassed in a radical radiotherapy field or with co-morbidity. An MRC study showed that for such patients with performance status 0–1, high-dose palliative radiotherapy (39 Gy in 13 fractions, if no spinal cord in the field or 36 Gy in 12 fractions, if cord in the radiotherapy field) results in better 2-year survival (13% vs. 9%) compared with 17 Gy in two fractions. Patients who need relief of local symptoms due to primary tumour or metastases are treated with palliative radiotherapy. This is either 10 Gy single fraction (PS >2), or 17 Gy in two fractions (PS 2). The side effects of large fractions include nausea, acute chest pain and fever.

Relapsed pre-treated NSCLC

In the small number of stage IIIB/IV patients who have received previous platinum-based chemotherapy and relapse whilst still fit, second line chemotherapy can be considered. Docetaxel has shown good activity and improved median survival of 3 months over best supportive care in this subset of patients. Re-irradiation is an option if >6 months after previous radiotherapy and it is possible to avoid spinal cord.

Erlotinib has shown a survival advantage of 2 months and improved symptom control when used in combination with chemotherapy. In the UK, erlotinib is recommended as a clinically and cost-effective alternative to docetaxel for the second line treatment of NSCLC.

New agents

Understanding some of the molecular mechanisms in NSCLC has led to the development of new targeted therapies. The mechanisms of these are common to several malignancies (see Appendis, p. 370). The most successful agents in NSCLC are those targeted against the epidermal growth factor receptor (EGFR). Two oral drugs which inhibit the tyrosine kinase domain of the EGFR are erlotinib (Tarceva™) and gefitinib (Iressa™). Toxicity with these drugs is unlike standard chemotherapy drugs and includes a characteristic rash which often reflects drug activity, diarrhoea and pneumonitis (reported in gefitinib in a Japanese study). The patients most likely to benefit from these drugs are female, those with an adenocarcinoma (especially bronchoalvelolar subtype), be non-smokers and be Asian. At the molecular level, increased EGFR protein expression, gene amplification and the presence of EGFR mutations in the tyrosine kinase domain increase patient response. A recent comparative study of gefitinib with a combination of carboplatin and paclitaxel (IPASS study) has shown that gefitinib results in a better progression free survival in patients with EGFR+ tumours.

A randomized study (E4599) showed that a combination of bevacizumab (anti-VEGF) with chemotherapy improves survival by 2.3 months in patients with untreated advanced non-squamous cell lung cancer.

Small cell lung cancer (Figure 9.7)

Small cell lung cancer (SCLC) accounts for 20% of lung cancer. Up to 60% have extensive stage disease at diagnosis.

Figure 9.7 Management of small cell lung cancer.

Limited stage disease

The standard treatment for patients with good performance status (0–2) and no significant co-morbidity is combination chemotherapy with platinum regime with concurrent thoracic radiotherapy and prophylactic cranial radiotherapy.

In 5–10% of patients with SCLC limited to lung, diagnosis is established only after resection. These patients need adjuvant chemotherapy as there is high likelihood of development of distant metastasis. Role of surgery in early stage disease is not well established. Surgery following complete or partial response to chemotherapy is not beneficial.

Chemotherapy (Box 9.5)

Chemotherapy remains the mainstay of treatment of small cell lung cancer. Randomized trials have shown that multiple agent chemotherapy is better than single agent in terms of response rate and survival.

Meta-analysis showed that cisplatin regime results in higher response rate (69% vs. 62% p < 0.001) and lower risk of death at 12 months (OR 0.80 CI 0.69–0.93; p = 0.002) for both localized and extensive SCLC. Platinum based regime has less mucosal toxicity, less myelosuppression and is easier to combine with radiotherapy than anthracycline-based regimes. Though there is no conclusive evidence that carboplatin-etoposide is similar in efficacy to cisplatin-etoposide, the former regime is easier to administer and the current clinical practice resides with using cisplatin where survival is the primary aim and carboplatin where palliation is the primary aim.

There is no established role for maintenance chemotherapy and patients are treated with 4–6 courses of chemotherapy. Dose intensification leads to increased toxicities with no survival advantage over standard dose chemotherapy.

Radiotherapy

Thoracic radiotherapy

Thoracic radiotherapy is indicated for patients with limited stage SCLC. A meta-analysis showed that addition of radiotherapy reduced the risk of death by 14% which is equivalent to 5% absolute increase in 3-year survival. In terms of intra-thoracic control, there is 25% absolute improvement with addition of radiation at an expense of 1.2% absolute increase in the risk of treatment related mortality. Interruption of radiotherapy results in lower survival (median survival 14 vs. 16 months). Patients who continue to smoke during radiotherapy also have a lower survival (median survival 14 vs. 18 months).

While the optimal dose and fractionation of radiotherapy remains unclear, most clinicians use 40 Gy in 15–20 fractions over 3 weeks which is given concurrently with 1^st, 2^nd cycle of chemotherapy if feasible or at the end of the chemotherapy. Some others use a radiotherapy regime of 50 Gy in 25 fractions. One study shows that twice-daily concurrent radiotherapy is better than once daily radiotherapy.

Prophylactic cranial irradiation (PCI)

Brain metastases are present at the time of diagnosis of small cell lung cancer in up to 10% patients. Another 40–50% of patients develop brain metastases during the course of illness suggesting that brain metastases are a common cause of treatment failure.

A meta-analysis of PCI for patients with SCLC in complete remission showed that PCI reduces the risk of brain metastasis by 54%, the risk of death is reduced by 16%, contributing to an increase in 3-year survival of 5.4% (20.7% vs. 15.3%). There is no evidence of differential benefit with age or radiation dose. Though, optimal timing of PCI is not clear, it is recommended that PCI should be administered without delay after primary treatment. There is no conclusive data on optimal dose of radiotherapy. 30 Gy in 10 fractions over 2 weeks is the commonly used regime in the UK. Other regimes include 20 Gy in 10 fractions, 30 Gy in 15 and 36 Gy in 18 fractions. Since there is some concern about the risk of long term neurological toxicities such as cognitive impairment and ataxia, PCI may be avoided in patients older than 70 years and those with cerebrovascular disease.

Extensive stage

Chemotherapy is the main modality of treatment and a recent Cochrane review showed that in patients with extensive SCLC chemotherapy prolongs survival. One of the regimes shown in Box 9.5 is used.

In patients with extensive disease who achieve complete response at extra-thoracic sites after primary chemotherapy, thoracic radiotherapy improves survival to a similar extent as that of limited stage disease. A recent randomized study has shown that patients with extensive SCLC (aged 18–75 years) who had a response to chemotherapy, would benefit from PCI. Patients who received PCI has a lower risk of brain metastases (1-year risk of 15% vs. 40%), and better 1-year survival (27% vs. 13%). The commonly used radiotherapy regime in this study is 20 Gy in five fractions.

Second-line chemotherapy

The median survival following relapse after first-line chemotherapy is approximately 4 months. There are two groups: the sensitive group who have previously responded and who have had a relapse-free-interval of at least 3 months and the resistant group who do not fit in the sensitive group. The sensitive group may be re-induced with same type of first-line chemotherapy. Of patients with sensitive disease 30–40% respond to second-line chemotherapy (median survival 6 months), while less than 10% of patients with resistant disease will respond to chemotherapy. The commonly used second line chemotherapy regimes are CAV or oral topotecan (Box 9.5).

Prognostic factors and survival

In general, performance status is the best predictor of outcome in lung cancer. In early stage NSCLC, tumour staging and nodal status are important prognostic factors.

In advanced stage NSCLC, females have better prognosis. Significant weight loss (>10% within last 3 months) and large cell histology indicate poor prognosis. An early response to treatment implies a longer survival.

Good performance status, female gender and limited stage predict prolonged survival in small cell lung cancer.

5-year survival by non-small cell lung cancer by stage is as follows:

Stage I	60–80%
Stage II	25–40%
Stage IIIa	10–40%
Stage IIIb & IV	<5%

30–40% of limited stage SCLC patients survive 2 years median survival 18–20 months). Median survival of extensive stage SCLC is 10–12 months.

Special situations

Superior sulcus tumour

Superior sulcus tumour (Pancoast’s tumour) typically presents as T3/T4 lesion. Accurate staging is important in the optimal management of these tumours. Recent studies indicate that a subgroup of patients without distant metastasis can be managed with combined modality approach. A recent phase II study of concurrent chemoradiotherapy (two cycles of combination chemotherapy with cisplatin and etoposide and radiotherapy to primary tumour and supraclavicular fossa giving 45 Gy in 25 fractions) reported a complete resection of tumour in more than three-fourths of the patients and an overall 5-year survival of 44%. In this study, surgery was done 3–5 weeks after chemoradiotherapy and additional two courses of chemotherapy were given postoperatively.

Selected series of radical radiotherapy (60–66 Gy) alone report a 5-year survival of up to 40%.

In summary, patients with operable tumours and good performance status (0–1) are treated with chemoradiotherapy followed by surgery and postoperative chemotherapy. Patients with medically inoperable or locally advanced tumours with good PS are treated with either radical radiotherapy or chemoradiotherapy. Patients with metastatic disease or with poor PS are treated symptomatically.

Carcinoid tumours

Localized carcinoid tumour is treated with surgery. Typical carcinoids are low-grade malignancies which are usually treated with excision, with parenchyma-sparing sleeve or bronchoplastic resections indicated whenever possible. Atypical carcinoids are aggressive malignancies, and radical surgical resection is indicated. Locoregional failure rates of 8% have been reported for typical carcinoids and 23% for atypical carcinoids. Role of adjuvant treatment is unknown. Up to 64% of patients with atypical carcinoid can develop systemic metastases at a median time of 17 months after diagnosis.

Combination chemotherapy using the regimes as in SCLC is used to treat metastasis carcinoid.

Mixed small and non-small cell lung cancer

A small proportion of patients (2%) present with mixed small and non-small cell lung cancer. There is no clear recommendation for management of these tumours exists. Hence treatment should be individualized based on the stage of the disease and general condition of patients. Although, there is no role for surgery for pure small cell lung cancer; patients with localized mixed tumours may be candidates for aggressive surgery or chemo-radiotherapy (similar to NSCLC as it requires higher dose of radiotherapy for optimal long term control). Patients with poor performance status or metastatic disease are treated with palliative measures.

Lung cancer in never smokers

Never smokers are those who have smoked less than 100 cigarettes in their lifetime. Studies suggest that environmental tobacco smoke is a common cause of these cancers. Other risk factors may also contribute. Women are more commonly affected than men. Adenocarcinoma is more common, particularly the bronchoalveolar carcinoma subtype. Treatment is essentially the same as that of smokers. However, recent data suggest that this group of patients have a higher response rate and better survival with EGFR tyrosine kinase inhibitors such as erlotinib and gefinib (see IPASS study, p. 102).

Multiple primary lung cancer

2–4% patients can present with multiple primary lung tumour which can be either synchronous (detected simultaneously) or metachronous (detected after an interval). However it is often difficult to distinguish this from a metastasis from the lung tumour. Patients with multiple primary cancers are managed as two individual tumours.

NSCLC with solitary metastases

A small subset of patients present with isolated extrathoracic metastasis either after radical treatment or at presentation. Studies show that in patients with good performance status, resection of the lung tumour and metastasis with or without systemic treatment result in improved survival.

In patients with synchronous isolated adrenal metastases, this approach results in a 5-year survival of 10–23%, whereas in those with isolated metachronous adrenal metastasis occurring >6 months after initial curative treatment, the 5-year survival is around 38%. Of those with recurrence in <6 months, none survive for 2 years.

In patients with synchronous isolated brain metastases with complete resection of all disease, the reported 5-year survival is 21%. Hence synchronous brain metastasis in a fully staged (including PET scan) resectable stage I–II lung cancer patient with good performance status is treated with resection or radiosurgical ablation with complete excision of the primary tumour. They also need systemic treatment as well as whole brain radiotherapy (WBRT) after resection (conflicting results). Patients with metachronous brain recurrence after a curative resection are also considered for resection ± WBRT or radiosurgery.

Palliative care issues

Despite recent advances in treatment, many patients with SCLC and NSCLC will progress and eventually die of their disease. Patients with advanced disease can present with a number of problems which require specialist services.

• Bone metastases are very common and can result in pain and spinal cord compression (p. 328). Pain can be improved using radiotherapy with a single 8 Gy fraction or 20 Gy in five fractions for spinal cord compression.

• Haemoptysis: invasion of vessels by expanding tumours can result in haemoptysis which can be significant. Palliative radiotherapy (10 Gy single fraction) may alleviate the bleeding but other measures can be used, e.g. cryotherapy.

• Superior vena cava obstruction can occur and should be treated as an emergency (p. 337). Steroids should be given in the first instance and radiotherapy (20 Gy in five fractions) is successful at reducing symptoms in 60%.

• Hypercalcaemia can be due to bone metastases or the production of a PTH like peptide. It should be tested for regularly in advanced lung cancer to prevent it presenting as an emergency (p. 339). It is treated with hydration, bisphosphonates and treatment of the underlying cancer if that is possible.

• Stridor is a rare but distressing symptom caused by compression of the proximal airways, usually by tumour or lymph nodes. Initial supportive care includes assessment of the airway by otolaryngologist, steroids and oxygen (p. 339). If severe, heliox, a mixture of helium and oxygen where the small particle size of helium facilitates delivery of the oxygen, can be given. Treatment of the compressive lesion (e.g. radiotherapy to the nodal mass) may be the only option to prevent progression of stridor.

• Breathlessness is the most common symptom in advanced NSCLC and can be debilitating. Investigations should be done to rule out significant pleural effusion and pulmonary emboli as these are both treatable. Assuming the breathlessness is due to tumour progression and no further active treatment is possible, simple measures such as the use of a fan, teaching relaxation techniques and the cautious use of oral morphine, which causes dilatation of smooth muscle walls in blood vessels leading to an improvement in symptoms, can be helpful. Overall lung cancer patients often have an array of palliative care needs such that specialist in symptom control should be involved at an early stage.

Follow-up

Role of follow-up in patients after curative treatment for NSCLC remains controversial. For patients with potentially curative re-treatment, it is reasonable to cover routine follow-up 3–6 monthly for 2 years and 6–12 monthly thereafter, with clinical examination and radiological evaluation. The role of routine follow-up after treatment for SCLC is less clear.

Some evidence suggests that continued smoking adversely affects the overall prognosis and hence discouraged.

Mesothelioma

Introduction

Mesothelioma is an aggressive tumour arising from the cells of pleura and peritoneum. Currently just over 2000 new cases are diagnosed in the UK annually and the number of cases is expected to peak in 2015. In the USA, 2000 new cases are diagnosed annually and the incidence is declining. Widespread use of asbestos after World War II correlates with the anticipated increase in Europe within the next 15 years. The median age at diagnosis is 60 years and males are five times more commonly affected than females.

Aetiology

Mesothelioma is the most strongly linked cancer to occupation. It is estimated that 80–90% of mesothelioma cases or deaths in men are caused by occupational exposure to asbestos. The latency period after exposure ranges from 15–50 years. Shipbuilding and construction are the industries which used to involve high exposure of asbestos. Smoking does not increase the risk of mesothelioma. However, smoking combined with asbestos exposure increases the risk of lung cancer.

Pathogenesis and pathology

Pathogenesis

Amphiobile (blue and brown) asbestos is strongly linked to mesothelioma. It is postulated that the thin and long fibres of amphiboles when inhaled could penetrate and scratch the pleural surfaces. The chromosomal changes caused by fibres as they pierce the mitotic spindle as well as free radical formation from the fibres cause malignancy. The possibility of relationship between simian virus 40 (SV40) and mesothelioma is still debatable. Recent studies suggest a possible genetic susceptibility to asbestos-induced carcinogenesis.

Pathology

There are four histological subtypes of mesothelioma:

• Epithelial (40%) – associated with pleural effusions and better prognosis.

• Sarcomatoid (20%) – ‘dry’ mesothelioma.

• Mixed (35%).

• Undifferentiated (5%).

The important histopathological diagnosis is adenocarcinoma, which is differentiated immunohistochemically. Mesothelioma is positive for calretinin, WT1 (Wilms’ tumour 1) antigen, epithelial membrane antigen (EMA) and cytokeratin 5/6 and negative for cytokeratin 7, 8, 18 & 19, TTF-1, BER-EP4 (mostly), CEA and MOC. The converse is diagnostic of adenocarcinoma.

Presentation

The usual presentations are exertional dyspnoea, chest pain or pleural effusion. Weight loss, fatigue, cough and paraneoplastic fever are also common. Right hemithorax (65%) is more often affected than left (35%) and 3% cases are bilateral.

Investigations and staging

Imaging

Chest X-ray and CT scan (Figure 9.8) are the initial methods of imaging. Chest X-ray shows evidence of pleural thickening, pleural effusion and volume loss. CT scan shows unilateral pleural effusion, nodular pleural thickening and tumour encasement of the lung (‘rind like’ appearance – seen in 70% of cases) leading to contraction of hemithorax. Calcified plaques are found in 20% of patients. Chest wall invasion leads to obliteration of extrapleural fat planes, invasion of intercostal muscles, displacement of ribs, or bone destruction.

Figure 9.8 Imaging of mesothelioma.

PET scan is helpful in distinguishing benign from malignant pleural masses and to detect extrathoracic and nodal disease. Recent studies report increasing usefulness of PET scan in defining prognostic group and to assess response to chemotherapy.

Tissue diagnosis

Histopathological diagnosis should be made in all cases using cytological analysis of pleural fluid or pleural biopsy done either under radiological guided or by VATS. A cell block prepared from at least 500 ml of pleural fluid is often helpful.

Staging

Table 9.3 IMIG staging system for mesothelioma

Stage
Ia
T1aN0M0	Limited to parietal pleura; no involvement of visceral pleura.
Ib
T1bN0M0	Limited to parietal pleura: scattered foci involving visceral pleura.
II
T2N0M0	Ipsilateral pleura with (i) involvement of diaphragmatic muscle or (ii) confluent visceral pleural tumor or extension from visceral pleura into the lung parenchyma.
III
T3N0M0	Ipsilateral pleura with involvement of the endothoracic fascia, or extension into mediastinal fat or solitary resectable extension of chest wall or non transmural involvement of pericardium.
T1–3N1M0	Ipsilateral bronchopulmonary or hilar nodes.
T1–3N2M0	Ipsilateral mediastinal or internal mammary nodes/subcarinal nodes.
IV
T4N0M0	Diffuse or multiple chest wall involvement; transdiaphragmatic extension to peritoneum; direct extension to contralateral pleura; mediastinal organ extension; extension to spine; extension to internal surface of pericardium or involvement of myocardium.
Any T, N3M0	Contralateral mediastinal nodes; contralateral internal mammary nodes or any supraclavicular nodes.
Any T, Any N, M1	Distant metastases present.

Management

There is no standard of care and only a minority of patients (10–15%) are eligible for any potentially curative treatment. The majority of patients (85–90%) presents with advanced disease with medial survival of less than 12 months and 5-year survival of ≤1%. Suitable patients with stage I and II disease may be treated with radical surgery or multimodality treatment aimed at long-term survival.

Surgery

There are no randomized data on the benefits of surgery. Radical treatment involves resection of the entire parietal and visceral pleura en bloc with underlying lung, ipsilateral pericardium and diaphragm called extrapleural pneumonectomy (EPP). Historical series suggest 5-year survival of 10–20% with EPP. The MARS trial (Mesothelioma and Radical Surgery) is aimed to determine whether EPP is better than no surgery in terms of survival and quality of life. However the majority of patients are not suitable for such extensive surgery. It has a reported morbidity up to 60% and mortality of 3.4% in expert hands.

Palliative surgery involves pleurectomy or decortication. It is an option for palliation of breathlessness caused by effusion when standard treatment options failed. The exact benefits of these procedures are not well-defined.

Radiotherapy

Mesothelioma is not a radiosensitive tumour. However, radiotherapy is still used in the following settings:

• Prophylaxis of thoracic tract seeding – to avoid mesothelial cell seeding down the tracts after thoracoscopies and drains. There is no convincing evidence for this indication (three small trials; one showed benefit and two did not). Radiotherapy dose is 21 Gy/3 fractions over a week using electrons.

• Palliative radiotherapy –to relieve pain.

• Adjuvant radiotherapy following EPP – no randomized trial data. One phase II trial reported reduced local recurrence and prolonged survival.

Chemotherapy

Although chemotherapy is used a part of multimodality treatment, many regimes have poor response to treatment and severe toxicity. Many chemotherapy studies using single or combination regimens showed an objective response rate of <20% with no impact on survival. A systematic study suggested cisplatin as the most active single agent. The antifolate agent, pemetrexed, which inhibits enzyme thymidylate synthetase, represents the recent advance in chemotherapy. A recent randomized study of 456 patients with PS 0–1, cisplatin with pemetrexed vs. cisplatin alone showed a superior response rate (41.3 vs. 16.7%; p < 0.001), median survival (12.1 vs. 9.3 months; p = 0.02), and time to progression (5.7 vs. 3.9 months; p = 0.001). Neutropenia was the commonest toxicity in the combined arm. The recommended dose of pemetrexed is 500 mg/m² given IV on day 1 followed by cisplatin 75 mg/m² of each 21 day cycle for 4–6 cycles. There are no data on benefit of chemotherapy beyond six courses.

In elderly patients, carboplatin is often substituted for cisplatin and data from phase II studies suggest similar efficacy.

Palliative care

Recurrent pleural effusion is a debilitating problem. Talc pleurodesis seems to give the best results with low morbidity. Alternate option is PleurX catheters with repeated drains.

Management of other symptoms follows the same principle of any advanced cancer.

Prognostic factor and survival

There are two prognostic predictive models: EORTC and Cancer and Leukaemia group-B (CAL-B). EORTC system (Table 9.4) distinguishes patients with mesothelioma as good (median survival 10.8 months) and poor (5.5 months) prognostic groups, where as CAL-B distinguishes six groups with median survival ranging from 1.4 months to 13.9 months. Table 9.4 shows the EORTC prognostic index.

Table 9.4 EORTC prognostic index of mesothelioma

Prognostic factor		Score
Sex	Male	+0.60
Performance status	1 or 2	+0.60
Histological diagnosis	Possible or probable	+0.52
Sarcomatous type	Yes	+0.67
WBC count	>8.5 × 10⁹/L	+0.55
Calculate total score by adding all the individual scores which can be 0–2.94

Outcome measures	Good prognosis (total score ≤1.27)	Poor prognosis (total score >1.27)
Median survival	10.8 months	5.5 months
1-year survival	40%	12%
2-year survival	14%	0%

Medicolegal implications

Mesothelioma is a notifiable disease. Patients diagnosed to have mesothelioma are automatically eligible for some benefits and allowances.

Peritoneal mesothelioma

Mesothelioma can also arise from peritoneal and pericardial cavities. Malignant peritoneal mesothelioma consists of up to 10–15% of all mesotheliomas and presents with abdominal symptoms due to ascites and tumour mass. The majority of patients present with diffuse peritoneal mesothelioma which is characterized by multiple nodules involving the entire peritoneal surface. Tissue diagnosis is by biopsy and it is important to rule out associated pleural disease.

Treatment options include systemic chemotherapy, cytoreductive surgery with or without intraperitoneal chemotherapy and radiotherapy. Patients with good PS (0–1) with diffuse disease and no extraperitoneal spread are considered for maximal cytoreduction and intraperitoneal hyperthermic chemotherapy. The chemotherapy agent used is mitomycin C. A systematic review reported a median survival ranging from 34–92 months and a 5-year survival ranging from 29% to 59% with this approach. The perioperative morbidity varied from 25% to 40% and mortality ranged from 0% to 8%.

Other patients with good PS and inoperable tumours may be considered for chemotherapy with cisplatin and pemetrexed (reported median survival 13.1 months). Surgery alone may be adequate for indolent well-differentiated tumours and multicystic mesothelioma variants (both variants are common in young women and arise from the pelvic peritoneum).

Patients with poor performance status are treated with symptomatic and supportive care. The overall median survival is around 12 months.

New agents and future direction

Since the success of pemetrexed, there have been attempts to improve survival with targeted agents. Most mesotheliomas overexpress EGFR and there have been phase II trials with two EGFR small molecules, gefitinib and erlotinib. Gefitinib showed limited activity in less than 10% and erlotinib did not produce any responses. TKIs which act on the VEGF pathway have also been examined (p. 372). Both sorafneib and vatalanib have shown a small number of responses in pretreated patients. However, bevacizumab, the monoclonal antibody against VEGF, showed no improvement in survival or response when compared with chemotherapy alone in a randomized trial.

There is some interest in the antineoplastic ribonuclease, rapirnase, which is isolated from frogs’ eggs. In 81 patients who had evaluable disease and progressed after chemotherapy, there were four partial responses, two minor responses and 35 patients achieved stable disease with a median overall survival of 6 months.

Thymoma

Introduction

Thymoma is an epithelial tumour arising from the thymus accounting for nearly half of all primary mediastinal tumours. It presents with a spectrum of manifestations and has a wide ranging prognosis from benign to highly malignant.

The peak incidence if thymoma occurs at 40–60 years, with no predilection for gender. There is no known aetiological factor.

Pathology

WHO classification (Box 9.6) which correlates with prognosis, is based on the histological assessment of morphology of the neoplastic epithelial cells and the non-neoplastic lymphocytic component.

Box 9.6
WHO classification of thymoma

Presentation

Nearly 50% are asymptomatic with diagnosis being made incidentally. Common symptoms include chest pain, cough, dyspnoea, dysphagia, hoarseness, respiratory tract infections and superior vena caval obstruction. Various paraneoplastic syndromes can be associated with thymoma. About 30–40% of thymoma patients have myasthenia gravis and conversely, 10–15% of patients with myasthenia have underlying thymoma.

Investigations and staging

Imaging

In chest X-ray, large tumours are seen as mediastinal widening or anterior mediastinal mass (Figure 9.9A). The typical appearance in CT scan is a well-defined homogenous anterior mass lesion (Figure 9.9B) within a well-defined fibrous capsule. MRI scan is useful to evaluate mediastinal, cardiac and pericardial spread when CT findings are unequivocal.

Figure 9.9 Imaging in thymoma.

Tissue diagnosis

CT guided FNA is less reliable. CT-guided core biopsy can be safely performed for large tumours. When CT guided biopsy is inconclusive or when not feasible, anterior mediastinotomy is the next choice. Although VATS helps to provide a tissue diagnosis, a theoretical risk of pleural seeding exists. For small tumours excisional biopsy is advisable.

Staging

Thymoma is staged according to Masaoka staging (Box 9.7), which is a postoperative staging. Invasion is the most important prognostic factor.

Box 9.7
Masaoka staging of thymoma

Stage	Description
I	Macroscopically completely encapsulated with no microscopic capsular extension
IIa	Microscopic invasion through the capsule
IIb	Macroscopic invasion into mediastinal fat or pleura
III	Invasion into adjacent structures (pericardium, lung or great vessels)
IVa	Pleural or pericardial metastases
IVb	Lymphatic or haematogenous metastases

Management (Figure 9.10)

Successful treatment of thymoma depends on complete surgical resection. The majority of thymomas confined to the thymus are amenable to curative resection. Stage-wise management of thymoma is shown in Figure 9.10.

Figure 9.10 Management of thymoma.

Early stage (stage I and II)

Surgery

En bloc surgical resection through a median sternotomy is the treatment of choice. Patients with myasthenia gravis or suspected to have myasthenia should have appropriate preoperative measures to avoid postoperative myasthenic crisis. Recurrence after complete excision of a stage I thymoma is less than 2%. 30% people will have invasive disease at surgery; still a complete resection can be achieved in the majority of these cases. However, recurrence of completely resected invasive thymoma is approximately 30% with median time of local recurrence around 3.8 years.

Radiotherapy

There is no proven role for radiotherapy in stage I disease. Previously, radiotherapy was considered as a standard adjuvant for stage II disease, as radiotherapy may reduce the risk of relapse from 26% to 5% in invasive disease. However, more recent studies challenge this approach as the most common mode of failure is pleural recurrence rather than mediastinal. Hence some recommend radiotherapy only if the resection margin is <1 mm and suggest histology should also be taken into account.

Chemotherapy

A subgroup of patients with pleural disease (IIb) are at risk of pleural relapse. These patients cannot be considered for radiotherapy because of the extensive radiation field, and hence may be considered for adjuvant chemotherapy.

Locally advanced disease (stage III and IVA)

If stage III or IVA with limited pleural disease is suspected preoperatively, patients should be treated with neoadjuvant treatment. This can be either chemotherapy alone (PAC) or chemoradiotherapy (EP with 45 Gy of radiation) (see below). Surgery is done 4–6 weeks after neoadjuvant treatment. Patients who haven’t had radiotherapy preoperatively, should be considered for postoperative radiotherapy (Box 9.8) provided the area of risk can be encompassed in a radical radiotherapy portal and pulmonary function tests are adequate.

Metastatic disease

Patients are treated with palliative chemotherapy if general condition permits. Otherwise treatment is essentially symptomatic and supportive.

Chemotherapy

Patients who fail surgery and/or radiotherapy or who present with metastastic disease are candidates for chemotherapy (Box 9.9). However, there are no randomized trials of chemotherapy in thymoma. Studies showed that a combination of cisplatin, doxorubicin and cyclophosphamide (CAP) resulted in an overall response of 50%, medial duration of response of 12 months and median survival of 38 months. Another combination regime of etoposide and cisplatin (EP) showed a response rate of 56% with median response of duration of 3.4 years and median survival of 4.3 years. Hence CAP and EP remains the standard chemotherapy combination for thymomas and thymic carcinoma.