CHAPTER 13. 2 Symptoms and signs (including SVCO) 287 Diagnosis relies on demonstrating reduced serum osmola- lity and sodium in the presence of inappropriately high urine osmolality and sodium excretion. Management with \202 uid rest riction is usually adequate but demeclocycline (which blocks the action of ADH in the dista l tubules) may be used in highly symptomatic cases. Small cell lung cancer presenting with LEMS has a better prognosis, probably due to its ear lier detection. Severely disabled patients may require plasma exchange or IV immunoglobulin s while oncological treatment is initiated. The other antibody mediated neurological syndro mes do not respond to these measures. Key points \200 Neurological paraneoplastic syndromes \200 Paraneoplastic syndromes do not independently pre- clude curative surgery. Most respond to conventional treatment of the underly- ing neoplasm. Found almost exclusively in SCLC and are auto-antibody mediated. It is useful to test for s peci \201 c auto-antibodies to make a positive diagnosis which often then leads to a searc h for an underlying malignancy. If speci \201 c auto-antibodies are present they can usual ly be identi \201 ed in serum, although CSF should also be obtained if the clinical pictur e is highly suggestive but the serum test is negative or there are any concerns regard- ing malignant involvement of the central nervous system or co-existent infective diagnoses. Other recognized paraneoplastic syndromes in lung cancer: Hematological \200 \200 \200 \200 Endocrine and metabolic \200 \200 \200 \200 \200 \200 \200 \200 Anemia Leukaemoid reactions Thrombocytosis Disseminated intravascular coagulation Hypoglycaemia Hyperthyroidism FSH/LH secretion Lactic acidosis Hyperuricaemia Carcinoid Syn drome Gynaecomastia Neurological syndromes and autoantibodies Syndrome Auto-antibody Renal \200 \200 Lambert \200\223Eaton- myasthenic syndrome P/Q type voltage gated calcium channel auto-ab. Glomerulonephritis Nephrotic syndrome Limbic encephalitis Anti-Hu (type-1 antineuronal nuclear auto-ab.) Cutaneous \200 \200 \200 \200 \200 \200 Hypertrichosis languinosa Erythema multiforme Tylosis Acanthosis nigricans Pruritus Erythro derma Cerebellar degeneration Anti-Hu Connective tissue \200 Dermatomyositis \200 Polymyositis \200 Vasculitis \200 SLE Autonomic neuropathy Anti-Hu Opsiclonus/ myoclonus Anti-Hu Further reading Anderson NE, Rosenblum MK, Graus F, et al. Autoantibodies in paraneoplastic syndromes associated with small-cell lung cancer. Neurology 1988; 38: 1391 \200\2231398. Retinopathy Retinal protein auto-ab. Anti CV2 auto-ab. Sensory-motor peripheral neuropathy Beckles MA. Spiro SG. Colice GL, et al. Initial evaluation of the patient with lung cancer. Symptoms, signs, laboratory tests and paraneoplastic syndromes. Chest 2003; 123: 1. Lambert \200\223Eaton myasthenic syndrome is the most common of the paraneoplastic neurolog ical phenomena. \200 Marra A. Eberhardt W. Pottgen C, et al. Induction chemotherapy, concurrent chemoradiation a nd surgery for Pancoast tumor. Eur Respir J 2007; 29(1): 117 \200\223126. Auto-antibodies to voltage gated calcium channels block acetylcholine release at the neurom uscular junction resulting in proximal muscle weakness, reduced tendon re \202 exes and au tonomic dysfunction. Weakness tends be worse in the lower limbs and transiently improves fo llowing repeated exertion (in contrast to myasthenia gravis). Rowell, NP. Gleeson, FV. Steroids, radiotherapy, chemotherapy and stents for superior vena caval obstruction in carcinoma of the bronchus: a systematic review. Clinical Oncol 2002; 1 4: 338 \200\223351. M PEAKE 288 13.3 Work-up of patients with a suspected diagnosis of lung cancer Overview Most patients with lung cancer have advanced disease by the time of diagnosis, lim iting the treatment options and prognosis. Early identi \201 cation and referral of high r isk individuals may improve the outlook for a proportion of patients. Treatment options are more varied and complex than in the past and depend on accurate assess- ment of disease st age and \201 tness for radical therapies. Multi-Disciplinary Lung Cancer Teams are, for t hese reasons, now at the core of the management of patients with lung cancer. be referred for their work-up to a rapid access clinic run by a specialist Multi-Disciplina ry Lung Cancer Team. Further investigation Blood tests There is currently no reliable tumor marker for lung can- cer. Biochemical abnormalities are relatively common and the most important include: \200 Hyponatraemia (resulting from inappropriate ADH secretion and seen in both non-small cell a nd small cell lung cancers). Hypercalcaemia (resulting from either bony metastases and the ectopic secretion of parathormone-like sub- stances; more common in squamous cell carcinoma s). Elevated alkaline phosphatase and lactate dehydrogenase (non-speci \201 c but associat ed with a poorer prognosis). Hypokalaemic alkalosis (resulting from ectopic ACTH secretion and strongly associated with small cell lung cancer). Risk factors The major risk factors for the development of lung cancer are: \200 \200 \200 \200 \200 Smoking (current or past). Age over 50 years. The presence of COPD. Previous exposure to as bestos. Previous history of head and neck and/or bladder cancer. Family history of lung can cer occurring under 50 years of age in a \201 rst degree relative. Mild normochromic anemia and leukocytosis are com- mon and a leuco-erythroblastic anemia ca n indicate bone marrow involvement. CT scanning A CT scan is the basic imaging modality for the diagnosis of lung cancer after the initial plain CXR and all but mori- bund patients should have a contrast-enhanced, stag ing CT scan of the thorax and upper abdomen (see Figs. 13.3.1 \200\22313.3.3). CT reports s hould include an assessment of the stage of disease. A CT scan should be carried out wherev er possible, prior to any invasive investigation. This is in order to reduce the number of diagnostic tests by maximizing the yield from tests such as bronchoscopy. Symptoms In its early stages lung cancer usually causes little in the way of symptoms; tumo rs can grow to a considerable size be- fore patients seek medical advice. Screening of asym pto- matic individuals is, as yet, of unproven value and is not likely to become routinely available in the foreseeable fu- ture. It is essential, therefore, that clinicians develop a high level of awareness of the early symptoms of the disease, the risk pro \201 le of th eir patients and understand the fact that curative treatment is more likely to be possible the earlier patients are referred to a specialist team. The com- monest symptoms are: \200 \200 \200 \200 \200 \200 \200 Haemoptysis. Cough. Breathlessness. Chest and/or shoulder pain. Weight loss. Hoarseness. Fa tigue. Many of these symptoms are non-speci \201 c and their onset is often gradual. The situatio n is made more complex because many smokers put down these early symptoms to the effects of smoking itself. It is important to remember that it is not only new symptoms that are of i mportance, but changes in chronic symptoms, such as cough. Referral and CXR The factors listed above have been encapsulated into guidelines for the re ferral of patients with suspected lung cancer by NICE. All patients where there is any susp icion of a diagnosis of lung cancer should have a plain chest X-ray. The vast majority of C XRs are abnormal in patients presenting with symptoms of lung cancer, but around 10% are no rmal, so it is important to remember that a normal CXR does not exclude the diagnosis. All patients should Fig. 13.3.1 CT scan (lung window) showing cavitating squamous cell tumor right lower lobe ( see Plate 8). CHAPTER 13.3 Work-up of patients with a suspected diagnosis of lung cancer 289 Biopsy of mediastinal lymph nodes. Options include: \200 Transbronchial needle aspiration (TBNA) using a Wang needle via a \202 exible bronchoscop e. Accessible nodes: sub-carinal, some pre-tracheal. Endobronchial ultrasound (EBUS) (see F ig. 13.3.5). Accessible nodes: sub-carinal, pre-tracheal, hilar. Endoscopic ultrasound (EUS ). Accessible nodes: inferior pulmonary ligament, AP window, sub-carinal. Surgical mediasti noscopy or mediastinotomy. Bronchoscopy with endobronchial biopsy. CT guided needle biopsy of pulmonar y mass (Fig. 13 .3.6). Open surgical biopsy with frozen section (with the option of proceeding to resection ). \200 NB: sputum cytology is now considered of little value in the diagnosis of lung cancer and s hould not be used routinely. It may be useful in a small proportion of patients un \201 t for other, more invasive, investigations. Fig. 13.3.2 CT scan (mediastinal window) showing bulky mediastinal and right hilar lymphade nopathy in a patient with small cell carcinoma. Fig. 13.3.4 US image of FNA in deep cervical lymph. Fig. 13.3.3 CT scan: sagittal reconstruction showing right apical (Pancoast) tumor invading into chest wall. Tissue diagnosis and staging Wherever possible the method of biopsy should be chosen to arr ive both at a tissue diagnosis of the tumor and the stage of the disease. To achieve this, the site of the most advanced disease that is amenable to biopsy should be targeted. The va rious biopsy options are listed below in the order of priority broadly in line with this pr inciple: \200 \200 Biopsy of a metastasis (e.g. skin, liver). Diagnostic pleural tap or image-guided pleural b iopsy in patients with a pleural effusion. Biopsy of supra-clavicular lymph nodes either by : \200 \200 Fig. 13.3.5 Operational tip of an Endobronchial Ultrasound Bronchoscope (EBUS) (Image court esy of Dr Robert Rintoul). Needle biopsy of palpable nodes or Ultrasound guided FNA biopsy of impalpable nodes (presen t in approximately 50% of patients with bulky N2/N3 disease on CT scanning (see Fig. 13.3.4 ). M PEAKE 290 Fig. 13.3.6 CT-guided needle biopsy. Fig. 13.3.7 PET CT scan showing increased 5FDG uptake in left upper lobe mass and an unsusp ected solitary liver metastasis (see Plate 9). Other imaging modalities Positron emission tomography (PET) scanning PET scanning is a form of metabolic imaging which relies on the ability of malignant tissues to take up radiolabe lled glucose. The label that is used in lung cancer is 5Fluoro- deoxyglucose (5FDG) which, unlike glucose itself, once phosphorylated, is not further metabolized within the ma- ligna nt cells. This allows an image to be taken of 5FDG uptake in the cells. PET scanning with 5 FDG is non-speci \201 c in that many in \202 ammatory disorders will also take up the iso tope. In the context of lung cancer this means that dif- ferential diagnoses such as tuberc ulosis, sarcoidosis and other granulomatous diseases can lead to false positive results as can in \202 ammatory causes of mediastinal lymphad- enopathy such as the post-obstructive pneumonias seen in lung cancer. PET scanning is now usually combined with CT scanning to gi ve accurate anatomical correlation of the areas of 5FDG uptake and a typical PET-CT image i s shown in Fig. 13.3.7. PET-CT scanning has a greater sensitivity and speci \201 city than CT scanning alone for the assessment of enlarged mediastinal lymph nodes and can also dete ct unsuspected metastatic disease in around 10% of patients otherwise suitable for radical treatment. Most of the pub- lished evidence for the value of PET scanning in lung cancer is in NSCLC and its role in the management of SCLC is not well de \201 ned. The indications for PET scanning in NSCLC include: \200 CT and MRI scanning of the brain Cerebral metastases are common in lung cancer, particu- la rly as the disease progresses. There is no good evidence to recommend routine imaging of th e brain in all patients, though some centers carry it out routinely prior to sur- gery in a ddition to a PET scan. Certainly a brain scan should be carried out if there is the slighte st hint from the history or examination that the patient may have a cere- bral metastasis. MRI scanning has a better level of sensitiv- ity and speci \201 city and it the scanning m odality of choice if available (see Fig. 13.3.8). In the \201 nal staging of all patients potentially suitable for radical treatment includ ing: \200 \200 \200 In the assessment of some indeterminate pulmonary nodules To asse ss the response after primary chemotherapy or radiotherapy in patients being considered for radical sec- ond-line treatments surgical resection radical radiotherapy combination chemo-radiotherapy Fig. 13.3.8 CT brain showing ring enhancement of a cerebral metastasis on the right and cer ebral oedema adjacent to a left sided metastasis (not itself shown in this image). PET scanning is unreliable for the detection of cerebral metastases. CHAPTER 13.3 Work-up of patients with a suspected diagnosis of lung cancer 291 Co-morbidities and \201 tness for surgery The median age at diagnosis of patients with lu ng cancer in the UK is 71 years and this, combined with the high prevalence of a history of cigarette smoking means that co-morbidities are common. In particular COPD and is- chaemic heart disease commonly make the diagnosis stag- ing and treatment of this patient group mo re complicated. The single most important investigation is the FEV1. In gen- eral, the pati ent may be considered for a pneumonectomy if the FEV1 is more than 2 litres and for a lobec tomy if more than 1.5 litres. At levels lower than these, further assess- ment of the pulmo nary function is usually required and may include one or more of the following: \200 Isotope bone scanning The skeleton is also a common site for metastasis in lung cancer. PET scanning will detect bony metastases of any signi \201 cant size, but in patients with bo ne pain who do not require a PET scan for any other reason, an Isotope Bone Scan is useful both for con \201 rming metastatic disease as the source of the pain and for detecting occ ult bony metas- tases which may need treatment to prevent pathological fractures. Staging systems Small cell lung cancer CLC is usually staged using the Veteran \200\231s As sociation 1973 classi \201 cation which divides cases into the following de- scriptive gro ups: \200 Full lung volumes (ideally using helium dilution and body plethysmography). Gas diffusion c apacity. Arterial blood gasses. An assessment of exercise capacity (which may include forma l exercise testing). Quantitative perfusion lung scanning. Limited disease: tumor limited to one hemithorax with regional lymph node metastases includ ing hilar, ipsilat- eral or contralateral mediastinal nodes and/or supracla- vicular node i nvolvement. Extensive disease: tumor beyond the con \201 nes of lim- ited disease. \200 \200 For the assessment of cardiac \201 tness there may be the requirement for echocardiograph y and/or coronary angiography. Assessment of \201 tness for treatment Performance status The functional status or performance status (PS) of a lung cancer patient is central to the assessment their \201 tness for chemotherapy and radical radiotherapy and is a powerful predictor of survival. It is de \201 ned as \200\230a measure of how well a patient is ab le to perform ordinary tasks and carry out daily activities \200\231. The commonest scoring system in use in the UK is that proposed by the WHO which is divided into the categories s hown in Table 13.3.1: Multi-disciplinary team (MDT) working As stated earlier in the chapter, the complexity of m odern diagnosis, staging and treatment means that no one indi- vidual specialist has all th e skills and experience to prop- erly assess the needs of a lung cancer patient. The MDT is the way that such expertise and complex decision-making is now organized and the managemen t of all lung cancer patients should be decided within that forum. Table 13.3.1 The WHO PS scoring system Patient information and support Because of the complexity and relative speed of the mod- er n work-up of lung cancer patients, they and their carers require careful verbal and written information and support throughout the care pathway. They usually meet a number of differe nt doctors along the way and the lung cancer Specialist Nurses are in the best position to identify and provide the timely support that is required over this dif \201 cult time. Score Description 0 Fully active, able to carry on all pre-disease performance without restriction 1 Restricted in physically strenuous activity, but ambulatory and able to carry out work of a light and sedentary nature (e.g. light house work, of \201 ce work) 2 Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more than 50% of waking hours. Further reading British Thoracic Society & Society of Cardiothoracic Surgeons of Great Brit ain and Ireland. BTS guidelines on the selection of patients with lung cancer for surgery. Thorax 2001; 56(2):89 \200\223108. Kumaran M, Benamore R E, Vaidhyanath R, et al. Ultrasoun d guided cytological aspiration of supraclavicular lymph nodes in patients with suspected l ung cancer. Thorax, 2005; 60: 229 \200\223233. 3 Capable of only limited self-care, con \201 ned to bed or chair more than 50% of waking ho urs. 4 Completely disabled. Cannot carry on any self-care. Totally con \201 ned to bed or chair. National Institute for Clinical Excellence. Diagnosis and treatment of lung cancer. London, 2005. Available at: www.nice.org.uk National Institute for Healthcare and Clinical Excelle nce. Referral for suspected cancer. London, 2005. Available at: www.nice.org.uk Patients with a PS of 0 or 1 are usually considered good candidates for chemotherapy, those with PS 2 as border- line and those with a PS of 3 or 4 un \201 t for anything but pallia tive treatments. M HEIGHTMAN & S SPIRO RICHARD HUBBORD 292 13.4 Treatment of non-small cell lung cancer Introduction Patients with NSCLC tend to present with advanced disease and it therefore rem ains a disease with poor prognosis, as shown by Fig. 13.4.1. Treatment selection is depende nt on staging and patient performance status and is best discussed at a multidiscipli- nary meeting. The staging system for lung cancer has up to now been based on a single center s experience of around 5000 cases. It has now been completely re-mapped by the International Association for the study of Lung Cancer (IASLC), a worldwide collaboration from 20 countri es and 45 different centers to include data from more than 100, 000 cases with all stages o f presentation of lung cancer. Table 13.4.1 summarizes the new clasi \201 cation and Table 13.4.2 the new stage groupings. N1 Metastasis in ipsilateral peribronchial and/or ipsilateral hilar lymph nodes and intrapulmo nary 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) Distant metastasis (M-factor) MX M0 Distant metastasis cannot be assessed No distant metastasis M1 Distant metastasis M1a Separate tumor nodule(s) in a contralateral lobe; tumor with pleural nodules or malignant p leural (or pericardial) effusion Table 13.4.1 IASLC staging project: TNM staging M1b Distant metastasis cTNM Clinical Classi \201 cation Primary tumor (T-factor) 1.0 TX Primary tumor cannot be assessed, or tumor proven by the presence of malignant cells in spu tum or bronchial washings but not visualized by imaging or bronchoscopy 0.9 0.8 0.7 y t i l i T0 No evidence of primary tumor 0.6 b a b o r p TIS Carcinoma in situ 0.5 T1 Tumor 3 cm or less in greatest dimension, surrounded by lung or visceral pleura, without br onchoscopic evidence of invasion more proximal than the lobar bronchus (i.e. not in the mai n bronchus) l a v v r u S 0.4 i IA 0.3 IB IIIB 0.2 T1a Tumor 2 cm or less in greatest dimension IIA 0.1 IIB T1b Tumor more than 2 cm but not more than 3 cm in greatest dimension IV IIIA 0.0 T2 Tumor more than 3 cm but not more than 7 cm; or tumor with any of the following features*: \200 6 7 8 9 10 11 0 1 2 3 4 5 Years Involves main bronchus, 2 cm or more distal to the carina Invades visceral pleura Associate d with atelectasis or obstructive pneumonitis that extends to the hilar region but does not involve the entire lung Fig. 13.4.1 Survival curves of NSCLC stages I-IV. Classi \201 cation from Mountain et al. 1997. \200 Table 13.4.2 IASLC staging project: Stage Grouping T2a Tumor more than 3 cm but not more than 5 cm in greatest dimension Occult carcinoma TX N0 M0 Stage 0 Tis N0 M0 T2b Tumor more than 5 cm but not more than 7 cm in greatest dimension Stage IA T1a, b N0 M0 Stage IB T2a N0 M0 T2 tumors with these features are classi \201 ed T2a if 5 cm or less Stage IIA T1a, b N1 M0 T3 Tumor more than 7 cm or one that directly invades any of the following: chest wall (includi ng superior sulcus tumors), diaphragm, phrenic nerve, mediastinal pleura, parietal pericard ium; or tumor in the main bronchus less than 2 cm distal to the carina but without involvem ent of the carina; or associated atelectasis or obstructive pneumonitis of the entire lung or separate tumor nodule(s) in the same lobe T2a N1 M0 T2b N0 M0 Stage IIB T2b N1 M0 T3 N0 M0 Stage IIIA T1, T2 N2 M0 T4 Tumor of any size that invades any of the following: mediastinum, heart, great vessels, tra chea, recurrent laryngeal nerve, esophagus, vertebral body, carina; separate tumor nodule(s ) in a different ipsilateral lobe T3 N1, N2 M0 T4 N0, N1 M0 Stage IIIB T4 N2 M0 Regional lymph nodes (N-factor) Any T N3 M0 NX Regional lymph nodes cannot be assessed Stage IV Any T Any N M1 N0 No regional lymph node metastasis CHAPTER 13.4 Treatment of non-small cell lung cancer 293 Table 13.4.3 Treatment of NSCLC by stage (from NICE guidelines 2005) Stage I Stage II Stage IIIA Stage IIIB Stage IV WHO 0 \200\2231 Stage IV WHO 2 Stage IV WHO >2 Surgery alone Radiotherapy followed by surgery Surgery followed by radiotherapy Preoperative chemotherapy then surgery a a a Surgery followed by chemotherapy Surgery then chemo- and radiotherapy a a Radical radiotherapy Chemotherapy and radical radiotherapy Chemotherapy a Symptomatic treatment/ palliative radiotherapy Key First choice for eligible patients Suitable for some patients Not recommended a Unless within a clinical trial NICE have provided extensive guidelines for the manage- ment of lung cancer (February 2005) . Their recommenda- tions for treatment according to stage are summarized in Table 13.4.3. Stage II A and B disease (see Table 13.4.2) \200 These patients should be considered for surgical resection with curative intent (although n o RCTs have compared surgery v other modalities). These tumors make up 15 \200\22325% of re sected cancers. Mean \201 ve-year survival is 45% for stage IIA and 33% for stage IIB wit h a survival advantage between 2 and 19% for T1 versus T2, (although larger tumors (T2b) do worse than smaller masses and are now closer in survival outcome to stage III A than II A) . T3NO survival is around 44% at 5 years. Sleeve lobectomy is an additional approach in cen trally located tumors when lung function makes pneumonectomy hazardous. This procedure is e specially useful for right upper lobe tumors that encroach onto the main bronchus, as they allow a cross sectional piece of airway plus the right upper lobe to be removed and the upp er and lower margins of the main airway are then reanastomosed. Studies have indicated comp arable mor- tality and long-term outcome. \200 Surgery Surgery offers the best chance of cure in patients with resectable disease. Typical ly this is in patients with stage I or II NSCLC but surgery is also sometimes indicated in more locally advanced disease. Stage I disease (T1a,b,N0,M0) or (T2a,N0,M0) \200 Surgery is the primary treatment choice, aiming for clear surgical margins and with curativ e intent. Mortality (death within 30 days of surgery) for all forms of pulmonary resection is 3.5% (systemic review of 16 studies; n = 41105), with a trend for increasing mortality w ith increasing age. Morbidity is 30% (higher for those with more extensive resections.) Fol lowing successful resection mean \201 ve-year survival for stage IA is 69% and for stage IB is 52%. Stage III A disease \200 Choice of operation \200 T3 disease or T1, T2 with mediastinal node involve- ment makes up about 10% of resected pat ients with NSCLC. This stage covers several presentations of lung cancer and making compari sons of results between centers more dif \201 cult. Completeness of resection and lymph no de status in \202 u- ence outcome signi \201 cantly. Prognosis seems to be worse when med iastinal structures are involved although there have been very few studies considering outc ome based on particular structures involved. Lobectomy is the procedure of choice (30-day mortality 3%). VATs lobectomy appears to be co mparable to conven- tional open lobectomy with potential lower morbidity and mortality. Mor e limited resection may be preferable if lung function is very impaired e.g. segmental rese ction (complete removal of a bronchopulmonary segment) or wedge resection (involving suturi ng or stapling across non ana- tomical planes). This can be either via thoracotomy or VATs procedure. Further studies comparing limited resection to lobec- tomy and VATs versus open thoracotomy are required. However local recurrence is commoner with wedge resection than wi th lobectomy. Distant recurrence can also be commoner if nodal dissection and staging are n ot done at segmental resection. Stage III A is a less heterogeneous group now that T3NO is classi \201 ed as II B \200 Outcome is particularly in \202 uenced by nodal status and many with bulky N2 disease will be considered unresectable. Surgery alone in those staged at IIIA preoperatively is associ ated with a relatively poor prognosis and such M HEIGHTMAN & S SPIRO 294 In a large series of patients undergoing pneumonectomy at the Mayo Clinic cardiopulmonary c omplications occurred in 38% of patients. Factors which adversely affected morbidity were a ge, male sex, associated respi- ratory or cardiovascular disease, smoking, decreased vital capacity and/or FEV1, reduced carbon monoxide single breath gas transfer factor, bronchial stump rein- forcement, crystalloid infusion and blood transfusion. Mortality was 4.6%, and factors that predisposed to death were cardiovascular disease, hematological disease, pre-o perative chemotherapy (not so in other studies), low hemoglobin, low gas transfer and a rig ht-sided pneumonectomy. patients require careful evaluation by the lung cancer MDT. Overall only 25% will be comple tely resectable and \201 ve year survival in those who are macroscopically com- pletely r esected is less than 25%. Some studies have looked at outcome of complete resection followi ng positive mediastinoscopy versus negative mediastinoscopy with the latter doing better ( \201 ve year survival 33% compared to 8-31%). Patients with negative staging tests but mic roscopic involvement of the mediastinal lymph nodes found in the pathological specimen afte r resection may have a \201 ve year survival of up to 40%. Radiotherapy Radical radiotherapy as sole treatment Radiotherapy has disappointed as a cura tive modality. For it to be successful the entire tumor volume (and any known metastatic di sease) has to be encompassed within the treatment \201 eld. However most of the earlier s tudies relied on CXRs to establish disease extent. Today, the use of CT and PET scanners al lows more precise staging and therefore better patient selection. It also allows more sophi sticated targeting of radiotherapy and therefore higher doses to be more safely given Radic al treatments incorporate at least 45 Gray (Gy) in 2 Gy fractions daily to the primary site . Studies using con- formal radiotherapy equipment can increase safe delivery to 75 or 80 G y. This has improved the local control of the cancer but the commonest cause of relapse is the appear- ance of distant metastatic disease. Stage IIIB \200 This incorporates patients with N2/3 disease and T4 tumors (trachea, carina, SVC, aorta, es ophagus, vertebral bodies) that are generally considered to be inoperable. One exception to this is patients with carinal disease in which resections can be performed by resecting th e carina and rejoining the main bronchi to the lower trachea. There is little data in this area but one systemic review of 8 series (n = 322) showed mortality of 18%, and 5-year surv ival of 27%. Mediastinal lymph node sampling at time of surgery All patients undergoing surgical resecti on should have systematic lymph node sampling to provide accurate pathological staging. It is not yet clear whether radical mediastinal lymphadenectomy or lymph node sampling offer a ny survival advantage over each other. There is little evidence that it does. Indications Stage 1 and II \200 Pre-operative assessment Whilst surgery offers the only realistic chance for cure, some pat ients are unable to tolerate lung resection. Pre- operative physiological assessment to pre dict post-operative lung function is therefore vital and is discussed in the section on the work up of lung cancer (Chapter 13.3). Radiotherapy is indicated in those who are \200\230medically inoperable \200\231 either be cause they are un \201 t for surgery or they decline it. There have not yet been studies d irectly comparing radical radiotherapy to surgery, palliative radiotherapy or no treatment. Overall survival post radical radiotherapy from numer- ous studies has shown a 1-year surv ival of about 70%, 2-year at 45%, 5-year at 17% (compared to 3-year survival of 0% with no treatment). There are very few studies comparing radiotherapy to surgery in comparable pati ents for obvious ethical rea- sons but those available show surgery to offer at least doubl e the chances of cure. However it is likely that those in the radiotherapy arms of such stu dies were less aggressively staged and also tended to be sicker and older than their surgic al counterparts. Post-operative complications \200 Factors predisposing to postoperative problems include smoking prior to surgery, COPD, dimi nished health status, poor nutritional status, advanced age and obesity. The length of the surgical procedure increases morbid- ity, with operations lasting more than 3 hours being t he critical cut off. Surgical complications include: injuries to the recurrent laryngeal an d phrenic nerves, broncho-pleural \201 stula, empyema and wound infection. Early complica tions following thoracotomy are: pulmonary atelectasis, nosocomial infections, respiratory failure and/ or persistent hypoxia, pulmonary embolism, aspiration pneumonia, acute lung in jury and cardiac arrhythmias. Stage IIIA and IIIB \200 As for Stage I and II disease, radical radiotherapy for stage IIIA and B has been disappoin ting. Two-year survival ranges from 12.5 to 24% (compared to 0 \200\2234% for untreated dis ease) and 5-year survival from 0 \200\22317% Outcome is more associated with disease bulk t han stage. For example a small T4,N0 tumor may have a better prognosis than more bulky earl y stage disease, which may involve too large a \201 eld to be safely irradiated. The pres ence of supraclavicular or contralateral hilar nodal involvement or pleural effusions would make patients ineligible for radical radiotherapy. Post-operative mortality \200 Post-operative mortality following thoracotomy is high. In large studies it is 5% at 30 da ys and 8% at 60 days, with a higher death rate for men than women. Mortality is higher for those over 70 years of age. In general mortality increases with disease stage, with a morta lity of 1 \200\2233% for those undergoing lobectomy for stage 1 disease. The major causes o f death are pneumonia, respiratory failure and cardiac events. \200 CHAPTER 13.4 Treatment of non-small cell lung cancer 295 There have been few studies documenting treatment related morbidity and quality of life. Continuous hyperfractionated accelerated radiotherapy (CHART) This has been a major potenti al advance for the adminis- tration of radiotherapy. In a large randomized trial of CHART v ersus daily conventional radical radiotherapy showed a signi \201 cant survival advantage for the experimen- tal arm, especially for squamous cell cancers, both for lung and head an d neck tumors. Treatment was given 3 times daily for 3 days at a rate of 1.5Gy every 8 hour s to a total of 54Gy. However this study has never been repeated and what might have become a treatment changing moment has been lost because of the dif \201 culty of radiotherapy u nits getting staff to cover the weekends necessary for treat- ment and \201 nding suf \201 cient patient numbers to make it more economically viable. Studies have now assessed C HARTWELL, i.e. CHART with weekend leave, and results may be comparable to the original tria l, but it remains a technique in danger of being abandoned. Palliative radiotherapy Radiotherapy remains excellent treatment for many of the manifestat ions of lung cancer as the natural history progresses: \200 \200 Provides relief from haemoptysis in 80% of cases. Relieves breathlessness from occlusion of large airways in 60%. Effective in treating enlarged lymph nodes, skin and bony metastases . For most cases a single fraction of 8Gy has been shown to be as effective as longer highe r dose courses, making only a single outpatient visit necessary. The same applies to pain f rom bony metastases, where one or two frac- tions a week apart are effective in up to 80% o f sufferers. Brain metastases: most early symptoms are due to cerebral oedema and if these resolve dramatically with steroids, ra- diotherapy tends to maintain this improvement for a few months. In those who respond poorly to initial steroids, the effects of radiotherapy a ppear less convincing. SVCO: radiotherapy may not relieve the symptoms if they have been es tablished for some weeks; stenting the SVC is often more effective. If, however the SVCO is treated early, radiotherapy can provide good control. Usually at least 20Gy in 5 fractions are needed. Combination of radiotherapy with chemotherapy Given that the main reason for treatment fail ure is distant relapse, radiotherapy is now being combined with chemo- therapy. There have been several trials assessing the ideal timing of the two modalities, either sequential wit h radio- therapy following chemotherapy, or concurrent, with chemotherapy starting at the c ommencement of radio- therapy. This timing question has not been adequately answered yet, a lthough concurrent treatment looks more promising. Chemotherapy General indications The main role of chemotherapy is in patients with advanced disease (stage IIIB and IV). Here chemotherapy can provide symptom relief, improve disease control, bet- ter quality of life and increase survival. However, only about a third of pa tients with this stage of disease are \201 t enough to receive systemic treatment. NICE h ave esti- mated that 1000 \200\2235000 patients receive chemotherapy each year yet over 16, 000 patients are eligible in terms of disease stage to receive it. Chemotherapy is generall y fairly well tolerated and given on an outpatient basis. A performance status of 0 \200 \2231 is recommended as these obtain the highest response rates and longer disease-free sur vival than those with per- formance status of 2 or worse (see Table 13.5.1, p. 298). Those with poor performance status have a lower response rate, shorter periods of disease control and a higher incidence of Grade 3 or 4 toxicity and risk of treat- ment related death. Oth er poor prognostic factors for patients with NSCLC receiving chemotherapy include male sex, metastases, increased LDH, >5% weight loss and patients >65 years of age. Neo-adjuvant radiotherapy There is no evidence that preoperative radiotherapy con- fers any survival advantage in NSCLC. It in fact may make surgery technically harder due to tissue \201 brosis. Adjuvant radiotherapy Again, there is no evidence that postoperative radiother- apy has any role. A large meta-analysis has shown that it may infact be harmful. Much of the data cons idered came from studies between 1960 and 90, and critics raise the problems of inadequate staging, however a more recent meta-analysis produced similar results, in particular sugges ting that adjuvant radiotherapy conferred a worse survival than no treatment post resection . For stage IIA disease, the possible role of adjuvant radiotherapy seems less harmful, but confers no survival advantage. Assessing suitability for radiotherapy All patients should undergo lung function tests, inc luding lung volumes and gas transfer factor. No minimum values for adequate lung function f or the size of planned radio- therapy \201 eld have been set and oncologists exercise cli ni- cal judgment in this assessment. In patients with FEV1 <1.0L radical radiotherapy is on ly suitable if the amount of normal lung irradiated is small. Patients should be strongly e ncouraged to stop smoking. Patients with poorer per- formance status do less well and treat ment is not usually recommended in those with performance status of WHO classi \201 cation of 2 or more (see Table 13.4.4). Weight loss prior to treatment is associated with poorer outcome. Increasing age does not appear to affect outcome. Second-generation agents Most important are the platinum based agents such as car- boplatin and cisplatin. Their use, in combination with one or two other drugs, has been shown to in crease median survival by 1.8 and 4.5 months (Cancer Care Ontario Prac- tice Guideline init iative: four meta-analyzes and eight randomized trials). There is signi \201 cant symptom relief as- sociated with treatment even in the absence of tumor shrinkage, but different tr ials have shown varying results for quality of life with either no change or an improvement . The platins are associated with side effects of nausea and myelosuppression. Nausea is im proved by co administration Complications Early complications include: oesophagitis (if the mediasti- num is included i n the \201 eld), skin reactions, pericarditis and, rarely, acute pneumonitis. Late compli cations include chronic pulmonary \201 brosis and late oesophageal strictures. M HEIGHTMAN & S SPIRO 296 of antiemetics and intravenous fluids. Carboplatin offers some advantage over cisplatin in that it can be used in patients with poorer renal function and without prehydration. A rece nt meta-analysis, however, appears to show some survival advantage with cisplatin compared to carboplatin. Survival bene \201 t with cisplatin may be most important in ERCC1 (a DNA repair protein) negative tumors, although more evidence is awaited. Other sec- ond line age nts include ifosfamide, vinblastine, vindesine, and mitomycin C. Successful regimens have i ncluded cis- platin, mitomycin C and a vinca alkaloid. and mutation level needs resolving. The potential role of these agents as \201 rst-line m onotherapy in patients with poor performance status, or as maintenance chemotherapy needs t o be explored.