Post-operative complications Bronchopleural \201 stula, respiratory failure, infection, p hrenic nerve damage causing diaphragmatic paralysis, recurrent laryngeal nerve damage causi ng hoarse voice, prolonged chest wall pain. Mortality: 1 \200\2233.5% for wedge excision, 2 \200\2234% for lobectomy, 6 \200\2238% for pneu- monectomy. Risk increases with increasing age, associated ischaemic heart disease, impaired respiratory function, and poor performan ce status. Following surgery Patients are often followed up by the chest clinic on a 6 \200\22312-mont hly basis for CXR review for 5 years (although there is no clear evidence on the necessity of such prolonged follow up in lung cancer). This is to ensure they are radiologically clea r of tumor recurrence, and there is not a second primary tumor. They should also be advised to seek earlier review if they have symptoms of persistent haemoptysis or new cough, weigh t loss, new chest pain. If histology shows incomplete resection margins, post-operative rad iotherapy would be given to try and improve local disease control. Further information BTS/SCTS. Guidelines on the selection of patients with lung cancer for surgery. Thorax 2001; 56: 89 \200\223108 CHAPTER 31 Lung cancer 292 NSCLC: chemotherapy Consider in patients with stage III \200\223IV disease, WHO performance status 0 \200\2232 (see p 295), even if they are asymptomatic from their cancer (greater t oxicity in those with poorer performance status). 40% respond tempo- rarily. Small improvem ent in symptom control and quality of life com- pared with best supportive care shown in RC Ts. Limited survival gains, 6 \200\2237 weeks compared with best supportive care. Median su rvival with chemotherapy in stage IV lung cancer: 10 months (Ps0), 7 months (Ps1), 4 months (Ps2). Combination chemotherapy (the use of more than one drug) is superior to single agent chemot herapy, improving survival rates when compared with single agent at 6 and 12 months (51% vs . 49% and 25% vs. 22%, respectively). \200 Commonly used \201 rst-line regimens include gemcitabine or vinorelbine plus a platinum-c ontaining drug (carboplatin or cisplatin), usually given for 4 cycles Side-effects Nausea, myelosupression, ototoxicity, peripheral neuropathy, nephropathy if dehydrated. No alopecia Patients are monitored during chemotherapy with repeat CT, usually after 2 cycles, to esta blish whether they have partial response, stable disease, or progressive disease, despite c hemotherapy. This CT in \202 uences decisions regarding further chemotherapy Second-line t reatments can be given in patients who relapse and are of good performance status. Taxanes (paclitaxel, docetaxel) are the most commonly used agents. These cause alopecia. Adjuvant therapy is the use of radiation or chemotherapy following complete surgical resect ion to improve survival. Adjuvant chemotherapy has been found to have signi \201 cant surv ival advantages compared with surgery alone in recent trials, including International Adjuv ant Lung Cancer Trial and Japan Lung Cancer Research group. Those with stage IB or stage II disease had a 69% 5-year survival vs. 54% in those treated with surgery alone. This treatm ent is now offered to patients with completely resected stage IB, II, and IIIa NSCLC. Adjuv ant radiotherapy trials have shown no evidence of a survival bene \201 t, except possibly in those with N2 disease. Should only be given in the context of a trial. Neo-adjuvant chem otherapy uses a non-surgical therapy (radio- therapy/chemotherapy) as the initial treatment . Pre-operative chemo- therapy has been shown in the recent multi-center LU22 trial to down stage a third of patients, but with no improvement in survival vs. surgery alone. Post-oper ative complications and quality of life were no worse in the chemotherapy group. A subseque nt meta-analysis suggested a 12% survival bene \201 t when compared with surgery alone, eq uivalent to 5% improve- ment in 5 year survival. It is important, however, not to delay sur gery and it is unclear as yet whether these results will change current practice. Chemother apy may also be given in the context of a trial, if surgery is not initially feasible due t o stage IIIa disease, aiming to downstage the tumor and allow resection. Unclear survival b ene \201 ts thus far. NSCLC: CHEMOTHERAPY 293 EGFR inhibitors EGFR (epidermal growth factor receptor) is an important mediator of cell gr owth, differentiation, and survival. It is over- expressed in 40 \200\22380% of NSCLC patie nts. New EGFR inhibitors include: \200 Ge \201 tinib (Iressa) Oral preparation used vs. placebo in patients refractory or intoler ant of their latest chemotherapy. No signi \201 cant difference in median survival time be tween the two groups Erlotinib (Tarceva) Shown to signi \201 cantly improve survival in pa tients with previously treated stage IIIB or IV NSCLC vs. placebo (6.7 vs. 4.7 months, p = 0.001). No bene \201 t shown in combination with chemo- therapy as a \201 rst-line treat ment. Used as second- or third-line therapy in NSCLC, but funding issues in UK. Response evaluation criteria in solid tumors (RECIST) \200\224 method of measuring response of a tumor to treatment (particularly in chemotherapy trials) Target lesion = all measurable lesions up to a maximum of 5 lesions per organ and 10 lesion s in total, representative of all involved organs. Record and measure sum of their longest diameter. Non-target lesions = all other sites of disease, which are recorded at baseline. Measurements of these lesions are not required, but presence or absence of each is noted du ring follow-up. Evaluation of target lesions \200 \200 Complete response (CR) \200\224disappearance of all target lesions Partial response (PR) \200\224at least a 30% decrease in the sum of the longest diameter of target lesions Progre ssive disease (PD) \200\224at least a 20% increase in the sum of the longest diameter of ta rget lesions Stable disease (SD) \200\224neither suf \201 cient shrinkage to qualify for P R, nor suf \201 cient increase to qualify for PD. Evaluation of non-target lesions \200 Complete response (CR) \200\224disappearance of all non-target lesions and normalization of tumor marker level Incomplete response/stable disease (SD) \200\224persistence of one or m ore non-target lesion(s) and/or maintenance of tumor marker level above the normal limits P rogressive disease (PD) \200\224appearance of one or more new lesions and/or unequivocal pr ogression of existing non-target lesions. Further information Burdett S et al. Chemotherapy and surgery vs. surgery alone in NSCLC. C ochrane Database Syst Rev 2007; 3: CD006157 Gilligan D et al. Pre-operative chemotherapy in patients with resectable NSCLC. Lancet 2007 ; 369: 1929 \200\22337 The International Adjuvant Lung Cancer Trial Collaborative Group. Cisplatin-based adjuvant chemotherapy in patients with completely resected NSCLC. NEJM 2004; 350: 351 \200\22360 NSCLC Collaborative Group. Chemotherapy in NSCLC: a meta-analysis using updated data on ind ividual patients from 52 randomized clinical trials. BMJ 1995; 311: 899 \200\223909 CHAPTER 31 Lung cancer 294 NSCLC: radiotherapy May be given for: \200 \200 \200 Curative intent (high dose) Palliative control (high dose) Symptom relief (low dose). Radiotherapy has no bene \201 t following complete primary tumor surgical resection. CHART (continuous hyperfractionated accelerated radiotherapy) is high- dose radiotherapy gi ven with curative intent. \200 Recommended for patients with localized chest disease <5 cm, stage I \200\223II with perfor mance status 0 \200\2231, who are resectable, but un \201 t for surgery or do not want sur gery Small radiation doses tds for 12 days (54 Gy in 36 fractions over 12 days) Patients ar e often in-patients for the duration of their therapy to facilitate their frequent radiothe rapy sessions Less morbidity than conventional radical radiotherapy A large randomized cont rol trial has shown an improvement in 2-year survival from 20% with conventional radical ra diotherapy to 29% with CHART. The largest bene \201 ts were in patients with squamous cell carcinoma. Overall 75% 1 year survival, 55% 2 year survival, 18% 5 year survival. Severe d ysphagia more likely with CHART in the \201 rst 3 months than with conventional radiother apy Need PFTs including lung volume and TLCO before CHART.FEV1 should be \211 1.5l Not per formed in all UK centers; lack of radiographers may limit availability. \200 High-dose palliative radiotherapy is given to patients with symptomatic disease, good perfo rmance status, no evidence of metastases, and who will be able to tolerate a high-dose regi me. An example of such a regime would be 36 \200\22339 Gy in 12 \200\22313 fractions over 6 weeks. Improves median survival by 2 months. Low-dose radiotherapy is given for symptom relief in patients who would be unable to tolera te high-dose palliative radiotherapy or those with evidence of metastases. Symptoms palliat ed include pain, haemoptysis, breathlessness, or cough. Urgent radiotherapy is used in combination with oral steroids for relief of superior vena c ava obstruction by tumor, although stenting performed via CT angiography is now the treatme nt of choice, where possible. Radiotherapy takes approximately 10 days to be effective. Chemoradiotherapy is used to improve tumor radiosensitization for localized disease. There may be some additional advantages with treat- ment of potential distant micrometastases. So me early survival bene \201 ts have been shown, and further studies are ongoing. Further information Saunders M et al. CHART vs. conventional radiotherapy. Lancet 1997; 350 : 161 \200\2235 NSCLC: RADIOTHERAPY 295 WHO/ECOG performance status 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 or 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 3 = Capable of only limited self-care, con \201 ned to bed or chair more than 50% of waking hours 4 = Completely disabled. Cannot carry on any self-care. Totally con- \201 ned to bed or chair Oken MM et al. Toxicity and response criteria of the Eastern Cooperative Oncology Group. Am J Clin Oncol 1982; 5: 649 \200\22355 CHAPTER 31 Lung cancer 296 Small cell lung cancer: treatment Surgery Limited stage small cell lung cancer may be appro priate for surgical resection if there is no evidence of metastases. This is rare. It requi res further assessment with brain and bone scanning bone marrow biopsy if there is an un explained abnormal FBC. The patient should also be considered for post-operative combinatio n chemotherapy for treat- ment of micro-metastases, especially if histology was only determ ined at operation. Chemotherapy Combination chemotherapy is used for limited and extensive SCLC. \200 \200 \200 \200 Etoposide with either cisplatin or carboplatin is the standard regime Given 3 weekly, commo nly for 6 cycles Different regimes are selected according to performance status Patients wi th performance status 3 may bene \201 t from less intensive out-patient chemotherapy on a 3 weekly basis Patients are carefully assessed and, if there is no sign of a response to tr eatment based on CXR or CT scan, they are switched to second-line agents, such as single ag ent topotecan or combination cyclophospha- mide, doxorubicin and vincristine 80 \200\22390% response if limited disease; 60 \200\22380% if extensive disease Chemotherapy may increase median survival to 12 months in limited disease. \200 Radiotherapy \200 Patients with limited stage disease who are reasonably well should have consolidation radio therapy to the chest disease, either with the \201 rst or second cycle of chemotherapy or after completion if they have a response or partial response Prophylactic cranial radiothe rapy is advised at completion of chemotherapy for those with limited disease or those with extensive disease and good prognostic factors. This improves survival by 5.4% In patients w ith extensive disease, including cerebral metastases, or poorer performance status, chemoth erapy is given \201 rst. If there is a good response, palliative thoracic radiotherapy ma y be given Of bene \201 t to symptomatic bone metastases, cord compression, SVCO. Further information Jackman DM, Johnson BE. Small cell lung cancer. Lancet 2005; 366: 1385 \200\22396 This page intentionally left blank CHAPTER 31 Lung cancer 298 Lung cancer: emerging areas Radio-frequency ablation (RFA) applied via a probe inserted int o a nodule/ tumor under CT guidance with sedation. Barbs/tines extrude from needle once in the tumor and cause tissue death by thermal necrosis. Lesions initially increase in size an d density, and may cavitate, but then become \201 brotic scar tissue. May become a tool t o treat patients with primary lung cancer unsuitable for curative surgery/radiotherapy due to comorbid disease, used with radiotherapy. The size of the cancer that can be treated is limited (maximum 5 cm, best results with <3 cm). Peripheral lesions are easier to access. S ide-effects of therapy: pleuritic chest pain, pneumo- thorax, haemoptysis, hemorrhage, low grade fever. FEV1 should ideally be >1 L. Tumor follow-up with contrast-enhanced imaging as ablated tissue does not enhance. Used currently mainly in pulmonary metastases from gastro intestinal or renal cell cancers, or sarcomas, which are not suit- able for surgical resect ion, but also some data for primary NSCLC. In 153 patients with primary or metastatic medic ally inoperable lung cancer, 78% 1-year survival rate, 57% 2-year, 27% 5-year (Simon CJ et al. Radiology 2007; 243: 268 \200\22375). No long-term RCT reported. Biological therapies such as oral thalidomide acting as an angiogenesis inhibitor are being tried. These may offer medium-term survival bene \201 ts in both SCLC and NSCLC. Targeted molecular therapy Lung cancer is said to be at the leading edge of targeted molecu lar therapy, which may become more effective than using traditional cytotoxic agents. The p resence or absence of these molecular target molecules seems to determine response to tradi tional treatments. The cellular targets under investigation include epidermal growth factor receptor (EGFR), protein kinase C, vascular endothe- lial growth factor, cyclo-oxygenase 2 , plus expression of various genes, including excision repair cross complementation protein gene, which has a role in DNA repair. Gene expression pro \201 ling may be used to determ ine the prognosis and response to therapy and to identify the mechanisms of tumor biology. In the future, lung cancer staging may also address the molecular biology of a tumor. Further information Dy GK, Adjei AA. Novel targets for lung cancer therapy. J Clin Oncol 20 02; 20: 2881 \200\22394 BTS Recommendations to respiratory physicians for organizing the care of patients with lung cancer. Thorax 1998: 53 (suppl. 1): S1 \200\2238 www.bacup.org.uk www.cancerguide.org www.cancerresearchuk.org www.lungcanceronline.org www.nice.org.uk/CG024NICEguideline www.roycastle.org, patient network, telephone 0800 358 7200 This page intentionally left blank CHAPTER 31 Lung cancer 300 Superior vena caval obstruction (SVCO): etiology and clinical assessment Obstruction of the \202 ow of blood in the superior vena cava results in the symptoms and signs of SVCO. It is caused by two different mechanisms (which may coexist): external compression or invasio n of the superior vena cava by tumor extending from the right lung (four times more common than the left lung), lymph nodes, or other mediastinal structure; or due to thrombosis with in the vein. Etiology The commonest cause is malignancy. Lung cancer and lymphoma together cause 94% of SVCO. Malignant causes \200 Lung cancer Up to 4% of lung cancer patients will develop SVCO at some point during their d isease. Up to 10% of small cell lung cancers present with SVCO Lymphoma Up to 4% of lymphom a patients will develop SVCO, most commonly in non-Hodgkin \200\231s lymphoma. This usually occurs due to extrinsic compression of the SVC by enlarged lymph nodes Other malignant cau ses Thymoma, mediastinal germ cell tumors, tumors with mediastinal metastases (commonest is breast cancer). Benign causes include granulomatous disease, intrathoracic goiter, and central venous lines , port-a-caths, and pacemaker wires (causing throm- bosis). In the past SVCO was commonly d ue to untreated infection, e.g. syphilitic thoracic aortic aneurysm or \201 brosing media stinitis (due to actinomycosis, tuberculosis, blastomycosis, or Aspergillus). These are all now rare. Clinical features \200 Facial and upper body oedema with facial plethora, often with increased neck circumference, and a cyanotic appearance Venous distension of the face and upper body. SVCO due to malign ancy usually develops over days to weeks, so an adequate collateral circula- tion does not have time to develop. Pemberton \200\231s sign \200\224facial plethora, distress, and somet imes stridor after lifting the arms above the head for a few minutes \200\224may suggest th e diagnosis Breathlessness Headache \200\224worse on bending forwards or lying down Cough/h aemoptysis or other signs of an underlying lung malignancy Hoarse voice Dysphagia Syncope/d izziness (reduced venous return) Confusion. \200 \200 \200 \200 \200 \200 Diagnosis is usually made clinically from the signs of facial and upper body swelling, with distension of super \201 cial veins across the chest wall, neck, and upper arms. SVCO: etiology AND CLINICAL ASSESSMENT 301 Investigations The investigation and treatment of SVCO was previously considered a medical emergency. SVCO is now not considered to be immediately life-threatening, making treatment less urgent and allowing a de \201 nitive diagnosis to be made prior to treatment. The exc eption to this rule is the patient who presents with stridor or laryngeal oedema, which is a medical emergency. \200 CXR Up to 85% have an abnormal CXR (as lung malignancy is the commonest underlying disorder ). Mediastinal widening is common CT chest with contrast can stage the underlying malignanc y and image the venous circulation and collateral blood supply Tissue diagnosis Usual pract ice is to obtain a tissue diagnosis of the underlying disease before starting treatment, as the underlying diag- nosis can alter treatment markedly. Symptomatic obstruction will have been developing for some weeks prior to presentation and, in the clinically stable patient , a delay of 24 \200\22348 h whilst the correct underlying diagnosis is obtained is warrant ed. Radiotherapy prior to biopsy can lead to problems making a subsequent histological diag nosis, and, similarly, high-dose steroids can make the diagnosis of lymphoma dif \201 cult Cytological diagnosis may be obtained from: \200 \200 Pleural \202 uid Ultrasound guided biopsy of an extrathoracic lymph node (e.g. supraclavi cular or cervical nodes \200\224low risk) Bronchoscopy, or mediastinoscopy if no endobronch ial disease, may be needed, depending on CT features. There may be increased risk of bleedi ng post-biopsy because of venous congestion, and anesthesia is theoretically more risky bec ause of possible associated tracheal obstruction or pericardial effusion (potentially leadi ng to haemodynamic compromise due to cardiac tamponade), though these can be anticipated fr om the CT scan Sputum 22 SVCO: management This is usually in two phases. \200 Initial general treatment: oxygen, analgesia, sitting the patient up (to reduce venous pres sure), and steroids (in some) Followed by treatment of the underlying disease causing the S VCO, dependent on the tissue diagnosis. The major differential in terms of treatment is sma ll cell carcinoma (initial chemotherapy), non-small cell carcinoma (initial radiotherapy), and lymphoma (chemotherapy). The presence of SVCO usually means that surgical resection of a NSCLC is not possible. CHAPTER 31 Lung cancer 302 22 SVCO: management (cont.) Steroids Limited trial data to support the use of steroids in SVCO, prior to de \201 nitiv e treatment, but most would start them fairly promptly (e.g. dexamethasone 8 mg bd, avoid i n the evening as affects sleep). They may reduce oedema and improve symptoms. Ideally a tis sue diagnosis should be obtained before commencing steroids, but may not always be possible . The problem arises where the underlying diagnosis is lymphoma, where steroids may alter t he histology, making a de \201 nitive diagnosis more dif \201 cult. In an older smoker, w ith an obvious CXR mass (in whom the diagnosis is likely to be lung cancer), steroids can p robably be started without risk to the underlying histology. Radiotherapy 90% of patients are oedema-free by 3 \200\2234 weeks. In those with a poor res ponse to radiotherapy, only 25% survive 1 year. Intraluminal stents are used for malignant SVCO, and may be a \201 rst-line treatment whi lst radiotherapy is planned. Successful in 90% of cases, with relief of symptoms in most pa tients within 48 h. They do not preclude sub- sequent radiotherapy or chemotherapy. In SCLC , however, chemotherapy will improve SVCO rapidly, so stent insertion may not be necessary. It is not clear whether post-procedure anticoagulation is required. Some centers advocate the use of low-dose warfarin anticoagulation (i.e. 1 mg/day), aiming for an INR of <1.6. Th rombosis in the SVC is not a contraindication to the procedure, as clot can be dispersed me chanically or with thrombolysis at the time of the procedure. Stent complications Stent mig ration is the major complication, but most patients do not live long enough for this to be a major problem. Anticoagulation Some recommend prophylactic anticoagulation in the presence of SVCO. Small increased risk of intracerebral bleeding, but the bene \201 ts of SVCO treatment may be li mited by subsequent SVC thrombus if anticoagulation is not started. This is controversial. SVCO due to thrombosis is usually in association with central venous lines or pacemaker wir es. If the clot is less than 5 days old (as judged by symptoms) thrombolysis is warranted. Subsequent oral anticoagulation may reduce recurrence. Prognosis depends on the underlying disease, and is unrelated to the duration of SVCO at pr esentation. The majority of SVCO is due to medi- astinal spread of carcinoma of the lung, s o the overall prognosis is generally poor, but depends on the patient \200\231s performance status, stage and extent of disease, and the cell type. Further information Rowell NP, Gleeson FV. Steroids, radiotherapy, chemotherapy and stents for SVCO in carcinoma of the bronchus: a systematic review. Clin Oncol (R Coll Radiol) 2002 ; 14: 338 \200\22351 This page intentionally left blank CHAPTER 31 Lung cancer 304 Hypercalcaemia De \201 nition and etiology A serum calcium level over 2.75 mmol/L is consi dered abnormal; borderline values need repeating. In malignancy, a raised calcium is due to increased osteoclast activity, either from bony metastases or the production of parathyroi d-hormone-related protein. A serum level over 3.25 mmol/L is rare outside malignancy, altho ugh can occur in sarcoidosis. Clinical features Values over 3 mmol/L are usually symptomati c. Common symptoms are confusion, weakness, nausea, reduced \202 uid intake, and constipa tion. There may be a short QT interval on ECG and renal failure. Investigations Exclude oth er causes of hypercalcaemia and identify the tumor, although in most patients with malignan t hypercalcaemia the diag- nosis of malignancy will already be known. The parathyroid hormo ne (PTH) will be suppressed in malignant hypercalcaemia, but raised in hyperparathy- roidis m. The phosphate will tend to be low in hyperparathyroidism and hypercalcaemia due to ectop ic PTH, and low/normal in sarcoidosis, meta- static bone disease, and with excess vitamin D . Check for renal failure. 22 Management of hypercalcaemia \200 Isotonic saline infusion (250 ml/h initially, to reverse dehydration, but avoid \202 uid overload, reducing to 150 ml/h) with furosemide to increase calcium excretion Steroids help , but less so than in sarcoid-associated hypercalcaemia, partly through reduced intestinal absorption. In addition to this initial management: \200 Reduce bone reabsorption with bisphosphonates (takes a few days for maximum effect). The bi sphosphonates can also reduce the pain of secondary bony deposits and may reduce pathologic al fracture rate. \200 Intravenous preparations Disodium pamidronate, 10 mL vial of 3 mg/mL, or 10 mL vial of 6 mg /mL infused over 2 h. Works for several weeks. Sodium clodronate, 300 mg (1 x 5 mL vial of 60 mg/mL) daily for 7 days or 1.5 g single dose (5 x 5 mL vials of 60 mg/mL). Zoledronic ac id, 4 mg vial reconstituted in water and given over 2 h, repeated monthly if required Oral preparations Sodium clodronate, one 800 mg tablet bd. This page intentionally left blank CHAPTER 31 Lung cancer 306 Syndrome of inappropriate secretion of ADH (SIADH) De \201 nition and etiology Excessive r etention of water relative to elec- trolytes due to inappropriate production of ADH. Hence there is hyponat- raemia (<135 meq/L), hypo-osmolality, a urine osmolality >100 mosmol/kg, a urine sodium concentration usually above 40 meq/L, normal acid \200\223base (and potassiu m), and usually a low plasma urea concentration. Diuretic- induced hyponatraemia will be ac companied by evidence of dehydration, e.g. raised urea. Causes of SIADH include: \200 \200 \200 \200 \200 \200 Drugs, e.g. carbamazepine, \202 uoxetine, high-dose cyclophosphamide Post major surgery P neumonia HIV infection CNS disorders, e.g. stroke, infection, psychosis Small cell lung can cer, either ectopic ADH production or stimulation of normal ADH production (poor prognostic factor). Clinical features Lethargy and confusion often when sodium levels fall below 130 meq/L and nearly always when below 120 meq/L. Investigations A low sodium in the presence of a low ur ea and an appropriate clinical setting may be adequate to make a diagnosis. If sodium deple tion/water overload are a possible alternative cause of hyponat- raemia, they should be acc ompanied by a urine osmolarity <100 mosmol/ kg (or a speci \201 c gravity <1.003 or a urin e sodium <40 meq/L). Therefore, values increasingly above this are suggestive of SIADH (unl ess the patient is on loop diuretics when, of course, the urinary sodium concentration will be higher). 22 Management of inappropriate ADH secretion \200 Fluid restriction (0.5 \200\2231.0 L/day) will help, but is often unpleasant for the patien t Demeclocycline (450 mg bd, tetracycline derivative) blocks ADH action at the distal renal tubules and can be used long term Salt tablets/extra-dietary salt May resolve over a few w eeks following chemotherapy Hypertonic saline is rarely indicated and can provoke brainstem damage (demyelination) through rapid changes in osmolality. \200 \200 Future developments New drugs speci \201 cally blocking the ADH receptor in the distal tub ule are under investigation. This page intentionally left blank CHAPTER 31 Lung cancer 308 Spinal cord compression This is a medical emergency requiring prompt treatment within 24 h to prevent irreversible paraplegia and loss of bowel and bladder function. De \201 nition and etiology Spinal cord compression occurs commonly in patients with metastatic cancer (in about 5% of all cancer patients, particularly breast, lung, and prostate cancer). It may b e the \201 rst presenta- tion of cancer, but often occurs in patients with a known primar y tumor. Cord compression is commonly caused by direct spread from a verte- bral metastasis into the extradural space or, less commonly, from pressure on the cord from a primary tumo r in the posterior mediastinum or the retroperitoneum, or by pressure from a mass of retrop eritoneal nodes. It is unusual to have a metastasis within the cord itself, although menin- geal spread can occur. Spinal cord compression causes interruption of the arterial supply to the cord and subsequent infarction. Clinical features Patients frequently experience bac k pain initially, due to associated vertebral collapse. This precedes any neurological sign s. Pain is not, however, universal. Neurological signs may be non-speci \201 c: weak legs, constipation, urinary incontinence. Leg weakness develops over hours \200\223days, with as sociated sensory loss. Loss of bladder and bowel sensation is a late sign and usually heral ds irreversible paraplegia within hours or a few days. Examination reveals bilateral upper motor neuron signs in the legs, with increased tone, weakness, brisk re \202 exes, and ext ensor plantars. There may be sensory loss in the legs, particularly with a loss of proprioc eption and a sensory level on the trunk. Sensory loss in the saddle area, with decreased re ctal tone, suggests a cauda equina lesion. The bladder may be palpable. Investigations Have a low threshold for investigating a patient with known cancer with back pain \200 MRI of the spine is the investigation of choice to demonstrate the level of the cord compre ssion CT is less reliable, but can also be helpful, if MRI is not available Plain spine XR may show vertebral metastases, but this is usually unhelpful, as there is no imaging of the spinal cord. Time should not be wasted in obtaining a plain XR Bone scan shows vertebral m etastases, but again does not image the spinal cord. Earlier scans showing bony metastases may alert the physician to the possibility of future cord compression If patient is not kno wn to have underlying malignant disease, a search for a primary tumor should be performed, but must not delay treatment of the spinal cord compression. Take full history (weight loss , anorexia, speci \201 c symptoms) and perform full examination, CXR, blood tests, PSA, an d myeloma screen. \200 SPINAL CORD COMPRESSION 309 22 Management of spinal cord compression This depends on tumor type and overall prognosis. Discuss with oncol- ogist and/or neurosurgeon to determine which de \201 nitive treatment( s) are the most appropriate for the patient. \200 High-dose steroids (dexamethasone IV 4 mg/6 h). These should be started whilst waiting for MRI scan, if the clinical picture suggests cord compression Radiotherapy to the metastasis or tumor causing cord compression, particularly if there are multiple sites of cord compres sion or if surgery is not advised Surgical decompression of the cord, reconstruction, and s tabilizing the spinal column Catheter if in urinary retention Care for pressure areas DVT p rophylaxis Consider chemotherapy, if appropriate, for underlying cancer causing the spinal cord compression, once the initial treatment has taken place Rehabilitation, ideally in uni t with spinal cord expertise. \200 \200 \200 Early referral to physiotherapists and occupational therapists with oncology expertise. A recent Dutch study showed 66% of patients with metastatic cord compression (from all canc ers) admitted to rehabilitation centers were dis- charged and the average survival post-dis charge was 808 days. 52% were alive at 1 year. Prognosis Patients who are mobile at present ation have the best prog- nosis and are likely to have preserved neurological function foll owing treatment. If there is some preserved motor function, 25% will be able to walk post-t reatment. If paraplegia is present pre-treatment, less than 10% will be able to walk afterw ards. Loss of bladder function for more than 24 \200\22348 h cannot be reversed. Further information Conway R et al. What happens to people after malignant cord compression ? Survival, function, quality of life, emotional well-being and place of care 1 month after diagnosis. Clin Oncol 2007; 19: 56 \200\22362 Eriks IE et al. Epidural metastatic spinal cord compression: functional outcome and surviva l after in-patient rehabilitation. Spinal Cord 2004; 42: 235 \200\2239 CHAPTER 31 Lung cancer 310 Pulmonary carcinoid tumors These are uncommon primary lung tumors, comprising 1 \200\2232% of all lung tumors. Equal male/female incidence; typical age at presentation is 40 \200\223 50 years. They are a form of neuroendocrine tumor and can have similar histological appeara nces to small cell lung cancer. Pathophysiology Although typically slow growing benign tumo rs, more aggressive subtypes exist, with metastatic potential. Commonly they are located en dobronchially, but can also be located peripherally in the lung parenchyma. Clinical features \200 Endobronchial carcinoids can cause isolated wheeze, dyspnoea, infection, haemoptysis, or pe rsistent lobar collapse Parenchymal carcinoids are often asymptomatic, being detected on ro utine CXR Carcinoid syndrome, with \202 ushing, tachycardia, sweats, diarrhea, wheeze, an d hypotension, occurs in 1% of pulmonary carcinoid tumors Carcinoid tumors can also be asso ciated with Cushing \200\231s syndrome, due to ectopic tumor ACTH production. Investigations \200 CXR may reveal a well-de \201 ned tumor, which should be further characterized on CT. Tumo urlets is the description given to multiple endobronchial or parenchymal carcinoid tumors. PET has decreased sensitivity for detecting carcinoid tumors compared with NSCLC (75% in on e study) Bronchoscopy is performed for accessible endobronchial carcinoid tumors. They typi cally appear to be intraluminal, cherry red, and covered with intact epithelium. Bronchial brushings may be adequate for a histological diagnosis. Bronchial biopsy can be associated with brisk or torrential bleeding, so care should be taken. Some avoid biopsy altogether an d proceed to surgical resection based on a clinical diagnosis. CT-guided biopsy may be pref erred for peripheral tumors Histological diagnosis can be dif \201 cult as the appearances can be similar to those of small cell lung cancer. Special stains and immunohisto- chemist ry are used to help differentiate between the two. Clinically, however, these tend to be qu ite different conditions and clinical details can aid pathological diagnosis. Carcinoid tum ors are characterized as being typical or atypical. They each have a characteristic pattern : \200 Typical carcinoids have no necrosis, occasional nuclear pleomor- phism, and absent or late mitoses. Distant metastases are rare and metastasis to lymph nodes occurs in 5 \200\22315% of cases. The 5-year survival is 100% and 10-year survival is 87% Atypical carcinoids may s how focal necrosis and often have nuclear pleomorphism. There is increased mitotic activity . They have distant metastases in 20% and metastasize to the lymph nodes in up to 48% of ca ses. The 5-year survival is 69% and 10-year survival is 52% PULMONARY CARCINOID tumors 311 Management \200 Patients with isolated pulmonary carcinoid tumors should be considered for surgical resecti on. Resection is ideally limited, removing minimal amounts of normal lung parenchyma. Tumor resection is associated with resolution of any features of the carcinoid syndrome If the t umor is atypical or close to the resection margin, patients should be followed up with repe at CXR on an annual basis. Radiotherapy is not performed Tumor size does not relate to the presence of lymph node metastases and therefore local lymph nodes should be sampled peri-op eratively In the 1% with carcinoid syndrome, serotonin antagonists, such as octreotide, can be used for treatment. Isolated liver metastases can be treated with arterial embolization . Metastatic aggressive carcinoid tumors can be treated with chemotherapy, such as etoposid e, cisplatin, 5- \202 uorouracil, and streptozotocin. Further information Hage R et al. Update in pulmonary carcinoid tumors: a review article. A nn Surg Oncol. 2003; 10: 697 \200\223704 CHAPTER 31 Lung cancer 312 Pulmonary nodules 1 De \201 nition These are focal, round, or oval areas of increased opac ity in the lung, measuring less than 3 cm in diameter. They are detected on CXR or CT. Grea ter use of CT and thinner slice spiral CT scanning has led to increased detection rates. CT allows the precise localization of a nodule and reliable determination of its features. It has a high sensitivity of detecting nodules of >5 mm in diameter. Volumetric analysis usin g CT-aided software means that a 3D nodule can be simulated, to aid nodule characterization and assess whether its volume has increased over time. Table 31.1 Causes of pulmonary nodules Benign Malignant Infectious granulomata Lung cancer Non-infectious granulomata Solitary metastasis Bronchial adenoma Benign hamartoma (developmental abnormality, containing cartilage, epithelium, and fat. Can contain smooth muscle. Slow growing. Can be seen at any age, especially 40+; often calcify .) The majority of pulmonary nodules are benign, although exact numbers depend on the characte ristics of the population screened 20 \200\22330% of patients with lung cancer may present with a solitary pulmonary nodule Of the nodules detected on CT in smokers with a normal CXR , between 1% and 2.5% will be malignant The Early Lung Cancer Action Project screening prog ram in the USA used CT scans in over-60-year-olds, with at least a 10-pack year history of smoking, and found non-calci \201 ed nodules in 23%, which were seen on CXR in 7%. 11% of these nodules were malignant on biopsy Early detection of these malignant nodules might alt er the management of the patient, with surgical resection of a stage 1 cancer. PULMONARY NODULES 1 313 Management options for patients with pulmonary nodules Observation Baseline CT scan showing nodule \211 4 mm, then repeat after an arbitrary tim e interval, such as 3 and 12 months, or 3, 6, and 12 months. If the nodule has increased in size or shows features of malignancy, con- sider biopsy or proceed straight to surgical re section. PET scan may be helpful in combination with CT if the nodule is indeterminate or i ncreasing in size, but cannot be biopsied. CT-PET scan useful in lesions >7 mm Biopsy Dif \201 cult on small nodules <7 mm, and those behind a rib or scapula. Resection If nodule has features of malignancy and biopsy not possible. Local practice vari es. Chemotherapy or radiotherapy If nodule proven to be malignant, but sur- gical treatment is not indicated due to performance status. Combined modality treatment CHAPTER 31 Lung cancer 314 Pulmonary nodules 2 Factors that suggest a pulmonary nodule is malignant \200 \200 \200 \200 Size >1 cm Smokers, older age Increasing volumetrically determined growth rates over time I ncreased enhancement with contrast, suggesting increased vascularity (>15 Houns \201 eld u nits) Increased FDG uptake with PET compared with normal tissue. Estimated sensitivity of P ET is 97% for identifying a malignant process Occult extrathoracic disease identi \201 ed on PET scanning Irregular or spiculated margin, with distortion of adjacent vessels \200 \224the \200\230corona radiata \200\231 sign Associated ground-glass shadowing Cavitation with thick irregular walls Pseudocavitation within nodule \200\224bronchoalveolar cell carc inoma. \200 \200 \200 Factors that suggest a pulmonary nodule is benign \200 \200 \200 \200 \200 