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. VEGF inhibitor (bevacizumab) VEGF is important in angiogenesis of tumors. This mono- clonal antibody that been shown to increased median sur- vival from 10 to 12.5 months when given in combination with standard chemotherapy for NSCLC. Squamous cell cancers were excluded fr om the trial due to increased incidence of bleeding complications in this group. Third-generation drugs Gemcitabine, paclitaxel, vinorelbine and docetaxel alone or in a two -drug combination, usually with a platin, have activity against NSCLC. To date trials have not demonstrated any clear advantage of any of these agents over another. NICE guidelines s uggest that optimum treatment is a single third-generation drug in combination with a plati n. Patients who cannot tolerate platinum based agents should be offered single agent chemot herapy with a third-generation drug. However several studies have compared platinum based r egimens to two other second- generation agents and no platin with no signi \201 cant diffe r- ences in survival. There is also no evidence that three-drug combinations are any better for survival than two-drug combinations. The appropriate length of therapy is generally ag reed to be 4 cycles, provided there is a response, or at least stable disease after the ini tial 2. More than 4 courses hardly affects response and increases toxicity. Combination treatment It is hoped that combination treatment might improve out- come compar ed to treatment with surgery or radiother- apy alone. There is evidence from other tumor ty pes that combination treatments may be of use. They can take three main forms: Adjuvant che motherapy/radiotherapy: cisplatin-based adju- vant chemotherapy can produce a signi \201 c ant survival ben- e \201 t of 5.3% after curative resection \200\223 can we add the stage i.e is Ia and 2 the same bene \201 t? Several studies have reported similar \201 ndings and post operative chemotherapy (probably 3 courses of a platinum containing regimen) will become the new standard. Neoadjuvant chemotherapy: there is some evidence to sug- gest tha t preoperative chemotherapy improves survival in early stage NSCLC. There have only been 2 large trials addressing this issue, but a meta-analysis has suggested up to a 5% advantage for neoadjuvant chemotherapy. There is no evidence that chemotherapy increases peri-operati ve complications, or adds to post-operative mortality. The studies have not contained enoug h patients to ascer- tain whether the bene \201 ts are greater for early or later stage re sectable patients. Three courses of platin based chemotherapy are recommended. Combined che moradiotherapy (for patients eligible for radi- cal radiotherapy, with treatments given eit her sequentially or concurrently). Primary concurrent cisplatin-based chemoradiotherapy for inoperable stage III NSCLC in- creases survival compared to radiotherapy alone, but can be accompanied by an increase risk of adverse effects. The effects on quality of life are not known. The present stand- ard of care for patients with stage III NSCLC and good performan ce status (0 \200\2231) is sequential chemoradiotherapy. By comparison, in primary chemothe rapy, treatment is given in the hope that there will be a tumor response and downstaging of their disease to allow them to proceed to curative surgery or radical radiotherapy. Second-line chemotherapy Docetaxel is the recommended agent for second-line treatment. When compared to best supportive care there was a 1-year survival bene \201 t (1-year survival 29% com- pared to 19%) as well as improved quality of life. Biological agents Epidermal growth factor receptor antagonists EGFR, a receptor tyrosine ki nase, is frequently over expressed in NSCLC and plays an important part in tumor cell survi val. Two agents have been studied thor- oughly in NSCLC, Iressa (ge \201 tinib); and Tar ceva , (erlo- tinib). Initial studies with ge \201 tinib showed that when given with init ial chemotherapy, there was no bene \201 t for adding the EGFR antagonist. Activity for bo th agents has only been demonstrated to date if the drug is given after relapse following 1 \200\2234 chemotherapy regimens. The most promising study (BR21) from Canada randomized pa tients with performance status 0 \200\2232 at relapse to erlotinib or placebo and showed im proved median overall survival from 4.7 to 6.7 months with better quality of life in those given erlotinib. A subsequent trial in a larger group of relapsed patients randomized to ge \201 tinib or placebo only showed trends to a prolonged survival with the active agent. S ubgroup analyzes in both trials showed signi \201 cant improvement in survival in Asian pa tients, especially women, those with adenocarcinomas and in non-smokers. Separate studies h ave shown dramatic responses to these agents when patients have somatic mutations in the EG FR gene, also seen most commonly in non-smokers and East Asian patients. However, despite t hese encouraging responses, patients almost always relapse within a few months. The overall importance of patients EGFR expressions status Lung cancer follow-up Follow-up depends on the treatment given and disease stage. It is imp ortant the follow-up plan is clearly commu- nicated to the patient at each stage. \200 Following surgery patients are seen 3-monthly for 2 years and then 6-monthly for up to 5 ye ars. There is no evidence of bene \201 t from follow-up beyond 5 years in those who remain disease-free. Two studies have shown no difference in survival with routine compared to sy mp- tom led follow up whilst one has shown better survival in those patients followed up re gularly. Following radical radiotherapy there should be 9 months of close follow-up with re gular CXRs to treat any pneumonitis, identify need for further treatment and CHAPTER 13.4 Treatment of non-small cell lung cancer 297 assess prognosis. Again there is no evidence of bene \201 t of follow-up beyond \201 ve years. Follow-up after chemotherapy is determined by antici- pated toxicity of treatment, u sually of the order of every 1 \200\2232 months for the \201 rst 6 months. Mountain CF, Dresler CM. Regional lymph node classi \201 cation for lung cancer staging. Chest 1997; 111: 1718 \200\2231723. NSCLC Collaborative Group. BMJ 199 5; 311: 899 \200\223909. NICE guidelines for the diagnosis and treatment of lung cancer 2005. PORT Meta-analysis Trialists Group. Postoperative radiotherapy in non small cell lung cance r; systematic review and meta-analysis of individual patient data from nine-randomized cont rolled trials. Lancet 1998; 352: 257 \200\223263. Those with advanced disease will need to be seen regularly because of the potentially rapid progress of their symp- toms and the likely need for palliation. There is evidence that nu rse led telephone follow up can be as effective, and preferred by patients on completion of palliative therapy such as chemotherapy. Saunders M, Dische S, Barett A, et al. Continuous hyperfraction- ated accelerated radiother apy (CHART) versus conventional radiotherapy in non-small-cell lung cancer: a randomized mu lti- center trial. CHART Steering Committee. Lancet 1987; 350(9072): 161 \200\223165. Further reading BTS guidelines on the selection of patients with lung cancer for Scullier JP. The staging of lung cancer. European Respiratory Monograph on Thoracic Malignancies. 3rd edn. 2009. surgery. Thorax 2001; 56: 89-108. Doroshow JH. Targeting EGFR in non-small-cell lung cancer 2005 Gilligan D, Nicolson M, Smith I, et al. Preoperative chemotherapy in patients with resectab le non-small cell lung cancer: results of the MRCLU22/NVALT 2/EORTC 08012 multicentre rando mized trial and update of systematic review. Lancet 2007; 369: 1929 \200\22337. NEJM, 353:123 \200\223132. Schiller JH. Comparison of four chemotherapy regimens for advanced non \200\223small-cell l ung cancer. NEJM 2002; 346: 92 \200\22398. Van Rens, M. Prognostic assessment of 2,361 pati ents who under- went pulmonary resection for non-small cell lung cancer, stage I, II, and I IIA. Chest 2000; 117(2): 374 \200\223379. Goldstraw P, Crowley J, Chansky K, et al. The IASLC lung cancer staging project: proposal f or the revision of the TNM staging group- ings in the upcoming (seventh) addition of the TN M classi \201 ca- tion of malignant tumors. J Thorac Oncol 2007; 8 (2): 706 \200\22314. M HEIGHTMAN & S SPIRO RICHARD HUBBORD 298 13.5 Treatment of small cell lung cancer Approximately 20% of all lung cancers are diagnosed as small cell lung cancer (SCLC). Aroun d 60% of these are classi \201 ed as extensive stage. Despite the simplicity of the staging system, there are other prognostic indicators for res ponse to treatment and survival. For example, good prognosis is conferred by a high perform ance status (e.g. ECOG 0-1, see Table 13.5.1 and Chapter 13.3 for the WHO classi \201 cati on) and normal values for sodium, albumin and alkaline phosphatase all of which contribute independently to survival. The combina- tion of performance status and these biochemical va lues can predict prognosis more closely than just dise-ase extent as determined from clinic al and radiological information. Staging The staging of SCLC has previously been more straightfor- ward than NSCLC, with div isions only into either \200\230limited \200\231 or \200\230extensive \200\231 stage dise ase. However, the new IASCL staging classi \201 cation (see Tables 13.4.1 and 13.4.2, p.29 2), when applied to SCLC does have some prognostic effects (Table 13.5.1), and although mos t centers are still using limited and extensive stage disease, this may change. \200 Treatment Chemotherapy Chemotherapy remains the mainstay of treatment in SCLC because of th e tendency for the tumor to metastasise early. Eligibility for chemotherapy depends more on prog- nostic features, especially performance status, rather than precise stage of disease . The greatest bene \201 ts from treat- ment are seen in patients with the fewest adverse prognos- tic features. Those with worse prognostic features can still achieve symptom palli ation and survival bene \201 t, but toxic- ity can be higher and the risks and bene \201 ts more \201 nely balanced. Established poor prognostic factors include performance statu s \211 2 (ECOG classi \201 cation), elevated LDH, extensive stage disease, and male sex. Limited stage: disease confined to one hemithorax (including pleural effusion) plus bilater al hilar or supra- clavicular lymphadenopathy. Extensive stage: metastatic spread outside t he thorax excluding hilar/ supraclavicular nodes. Given that two-thirds have extensive stage disease on pres- entation further investigation for distant metastases is always indicated (the most common sites being liver, adrenal glan ds, brain and bone) as outlined in the following \201 gure: Clinical evaluation for distant metastases \200 CT of chest, liver and adrenals \200 FB C/ LFTs/ U&Es /calcium \200 Selected imaging of any symptomatic area KEY FACT If the patient has good prognosis markers at presentation, the 3-year survival fol lowing treatment is about 15%. Disease extends outside a safe radiotherapy port? The natural history of untreated SCLC results in a median survival of only 4 \200\2236 mont hs for limited stage disease and 3 months for those with extensive stage disease. This chan ged with the development of single and then multiple agent chemotherapy in the late 1970s, which extended the survival \201 gures. Initial treatment was with drugs including methro trexate, cyclophosphamide, ifosfamide, adriamycin and vinca alkaloids. By the early 1990s p latinum based, two- drug combinations were shown to be as effective as \201 rst-line trea tment, and easier to give. Most studies have used cispla- tin rather than carboplatin and h ave shown survival bene \201 ts at 6 and 12 months in comparison to the older regimens. LIMITED STAGE EXTENSIVE STAGE Fig. 13.5.1 Staging tests for small cell lung cancer CT or MRI of the brain is not worthwhile in asymptomatic patients, unless there is weight l oss of more than 5 kg. Cycle number Initially chemotherapy was given until a complete response was achieved, or un til relapse if the response was only par- tial. However studies have shown 6 courses to be adequate; fewer courses caused the disease free period of respond- ers to be shorter than a fter 6 treatments. Maintenance therapy, even at a reduced intensity that initial \201 rst -line treatment does not improve overall survival Table 13.5.1 IASLC staging project : application of the proposed classi \201 cation to the data basis cases with small cell lung cancer. Stage n patients 1-year survival (%) 5-year survival (%) IA 211 77 38 IB 325 67 21 Dose intensi \201 cation This has been the subject of several studies, including bone marr ow harvesting followed by very intense chemother- apy. Other forms included late intensi \201 cation following conventional chemotherapy, weekly treatments, or initial intensi \201 cation. None of these approaches had any bene \201 t on survival. This suggests that, although one can kill large quantities of the tumor, resistant cells remain which continue to grow and cause relapse. IIA 55 85 38 IIB 270 70 18 IIIA 1170 59 13 IIIB 1399 50 9 IV 4530 22 1 From Sculier JP. Staging of Lung Cancer. European Respiratory Monograph on Thoracic Maligna ncies 3rd Edition, 2009 CHAPTER 13.5 Treatment of small cell lung cancer 299 death of 0.84 (95% CI 0.73 \200\2230.97;p = 0.01), which corre- sponds to a 5.4% increase i n the rate of survival at 3 years. Larger doses also reduced the incidence of relapse in th e brain, but no improved effect on survival. There is very little evidence pertaining to th e effectiveness of PCI in those with extensive disease on survival, although it almost cert ainly reduces the incidence of brain metastases. Second-line chemotherapy This is usually reserved for those patients who have had a good re sponse to \201 rst-line treatment and at least 3 months between the best response achieve d and progression. Studies have shown much more modest response rates compared to \201 rs t-line treatment in SCLC although at least equivalent to \201 rst-line chemotherapy in NS CLC. However, response is usually of short duration and there is no out- standing second-li ne regimen to recommend. Some re-in- troduce the initial chemotherapy following a period of disease control of at least 1 year, others use drugs such as topotecan or an older regimen to which the patient has not been exposed. Palliative radiotherapy As in NSCLC, radiotherapy is an excellent palliative treat- ment, e specially for symptoms caused by relapsing disease. It provides good control of haemoptysis , large airway narrowing, bone pain, superior vena caval obstruction, painful or unsightly lymphadenopathy and skin lesions and sometimes for brain metastases. For most of these, sin gle fractions of 7 \200\2238Gy are most effective and convenient. Radiotherapy SCLC is extremely radiosensitive and radiotherapy there- fore also plays an im portant role in treatment in a number of ways: Surgery Early data suggested that surgery had no place in the man- agement of SCLC with stu dies suggesting that patients fared no better than those treated by radical radiotherapy. S ince the development of better staging techniques and the understanding that SCLC is often disseminated at pres- entation the only small cell tumors that are excised are solitary nod ules diagnosed post-operatively, and carcinoid tumors in which histology obtained at \201 breoptic bron- choscopy was indistinguishable from SCLC. Nevertheless there are several se ries of resected, genuine SCLC and in general the median survival is better than that of li mited stage disease treated by chemotherapy with or without radiotherapy. Consolidation thoracic irradiation Review of several studies suggests that this provides a median survival bene \201 t of approximately one month and a 5% improvement in three year survival with the addition of radiotherapy to chemotherapy (19% v 14%). Many studies have s hown that thoracic radiation improves control of the primary disease and therefore local sy mptom control. However its effect on survival is minimized by the dissemi- nated nature of SCLC, with a subsequent high incidence of metastatic relapse. Most studies have reported on a dose range of 40Gy in 15 fractions over 3 weeks, to 50Gy in 25 fractions over 5 weeks. T he timing of the administration of thoracic radiotherapy in relation to chemotherapy has be en the subject of de- bate. Studies have compared early administration (during the \201 r st 9 weeks of chemotherapy) to late (after 9 weeks of chemotherapy). They have studied diff erent total doses and also different fractionation regimens including hyper- fractionated a ccelerated radiotherapy. Whilst the latter has been shown to improve survival compared to d aily admin- istration, a review of all available studies suggests that the most important f actor is getting all the intended chemo- therapy to the patient in timely fashion. If this is not achieved, then the timing of the radiotherapy doesn \200\231t ap- pear to be importa nt. Studies of radiotherapy timing in which all the chemotherapy was given to more than 80% of the patients had a 6 months better median survival com- pared to those where the chemot herapy was only fully given to less than 80% of patients. AUTHOR \200\231S TIP Provided optimal staging is performed on a known SCLC which looks oper able by lobectomy and that staging includes careful assessment and biopsy of mediastinal no des, patients can do well and should be considered for surgical resection. There is less evidence that downstaging with prior chemo- therapy effects cure when followe d by resection. There is also no study showing any bene \201 t for postoperative chem- oth erapy, as the numbers undergoing resection are too small for a randomized trial of adjuvant chemotherapy. Further reading Auperin A, Aup rin A, Arrigada R, Pignon J-P, et al. Prophylactic cranial irradiation for patients with small-cell lung cancer in complete remission. Prophylactic Cr anial Irradiation Overview Collaborative Group. NEJM 1999; 341(7):524 \200\223526. Prophylactic cranial irradiation (PCI) This is important given the frequency of cerebral me tas- tases in SCLC and the uncertainty of cytotoxic drugs crossing the blood brain barrier. PCI aims to eradicate microscopic disease before symptoms from brain metas- tases develop, and is usually most appropriate for those with limited disease who have had a complete res ponse to primary treatment. There is evidence to suggest that this should be given fairly s oon after completion of chemo- therapy, rather than delayed. Studies show that PCI reduces the incidence of brain metastases, by up to 54% in some studies. A recent meta analysis of more than 900 patients receiving PCI after achieving a complete response with chemotherapy found a reduction in the relative risk of Goldstraw P, Crowley J, Chansky K, et al. The IASLC lung cancer staging project: proposal f or the revision of the TNM stage group- ings in the upcoming (seventh) addition of the TNM classi \201 ca- tion of malignant tumors. J Thorac Oncol 2007; 8 (2):706 \200\22314. Pignon JP. Role of thoracic radiotherapy in limited-stage small-cell lung cancer: quantitat ive review based on the literature versus meta-analysis based on individual data. J Clin On col 1992; 11: 1819 \200\2231820. NICE guidelines for the diagnosis and treatment of lung cancer 2005. Spiro S, Souhami RL, Geddes DM, et al. Duration of chemotherapy in small cell lung cancer: a Cancer Research Campaign trial. Br J Cancer 1989; 4:578 \200\223583. F GLEESON 300 13.6 PET-CT Background Malignant cells are characteristically more glucose avid than non-maligant cells , and it is this that allows their de- tection using PET-CT scanning. They have up-regulate d glucose transportation receptors that increase their ability to concentrate glucose compa red to normal cells. PET scan- ning uses this malignancy trait to increase the concentra- t ion of trapped radiolabelled deoxygenated glucose to allow detection of malignant tissue. D eoxygenated glucose is radiolabelled with 18 \202 uorine to make 18FDG. This is injected into fasted patients. Between 40 to 60 minutes is then allowed with the patient resting bef ore scanning, allowing intracellular uptake and concentration of 18FDG and its metabolites to occur. After intracellular uptake, the 18FDG fails to be fully metabolized within the ce ll and ac- cumulates as 18FDG-6-phosphatase (FDG-6-P). As malig- nant cells are more glucos e and 18FDG avid than non- malignant cells the concentration of 18FDG-6-P is greater in mal ignant than benign tissue. Of note, it also greater in other metabolically active tissue su ch as the heart and brain, as well as in areas of in \202 ammation such as pneumo- nia, gr anulomatous reaction and post-radiotherapy. The 18FDG-6-P undergoes decay, producing a posi tron which immediately collides with an electron producing two photons. These photons are p roduced at 180 to each other, and are detected by the PET scanner. As more are produced i n areas of greater concentration of 18FDG-6-P the scanner detects more photon activity in a reas of malig- nancy and other areas of increased metabolic activity. 1. The solitary pulmonary nodule (SPN) SPNs detected on CXR and CT may now be investigated using PET-CT. The decision on whether to assume the SPN is benign, perform a follow-up CXR or CT, perform a bi- opsy, go straight to resection, or perform a PET-CT scan is dependent on patient preference and the clinical and ra- diographic parameters. The diagnostic accura cy of PET-CT is dependent upon: \200 The size of the nodule, with nodules <1cm in diameter more likely to be false negative. The position of the nodule, with smaller nodules less readily characterized within the lower l obes, due to respiratory motion. The cell type if malignant, with bronchoalveolar cell car- cinoma being a common cause for false negative scans. A meta-analysis reported a sensitivi ty and speci \201 city for malignancy of 93.9% and 85.8%. The value of PET-CT is in part d ependent on the pretest probability of malignancy. PET-CT may be used to con \201 rm a dia gnosis of benign disease in patients with a low pretest probability of malig- nancy. Genera lly the value of PET-CT in the management of SPNs is to obviate the need for biopsy. If a n odule is \200\230PET negative \200\231, it is likely to either be benign or of low grade m alignancy and may be followed up with a CT scan at one year. If a nodule is \200\230PET po sitive \200\231, resection is most commonly performed, as biopsy is unlikely to exclude mal ignancy in these circumstances. 2. Lung cancer staging PET-CT is used pre-radical therapy in clinically appropriate patient s with lung cancer. The PLUS study showed a 50% reduction in futile thoracotomies in patien ts that under- went PET scanning as part of their work up prior to surgery compared to thos e that had CT alone. The degree of primary tumor uptake is in part dependent on both the si ze of the tumor and the cell type. SCLCs are the most FDG avid. Its main role pre-radical t herapy is in the assessment of the mediastinum and detection of metastatic disease. It has also been shown to be of prognostic importance. There are a signi \201 cant number of addi tional abnormalities demonstrated on PET-CT scans when performed in patients with suspected or biopsy proven lung cancer. Technology The advent of PET-CT has allowed the anatomic localisa- tion of these areas with far greater precision than when PET was performed without CT. Consequently the diag- nosti c accuracy of PET-CT is far greater than PET alone. The ability to assess the metabolic act ivity of lymphaden- opathy seen on CT and the increased sensitivity of PET compared to CT i n most areas of the body has also resulted in PET-CT having a greater diagnostic accuracy f or lung cancer than CT. The use of CT has also reduced the total scan time. Measurement It is also possible to quantify the degree of FDG activity seen in areas of upt ake. Apart from quanti \201 cation meas- ures used in research, most reporters use the sem i- quantitative standardized uptake value (SUV). The SUV is reported from over a region of interest such as a lung cancer, and is calculated using the dose of 18FDG injected, and the patients bodyweight. The time from injection is an important variable that is recorded to allow the measure- ment to be repeated on follow-up scans if necessary. Various thresholds for reporting a nodule, mass or lymph node have been used, the most common being an SUV of greater than 2.5, although subjective analysis ie whether it looks \200\230hot \200\231 is possibly just as effective in experienced hands. Mediastinal assessment FDG-PET performance is dependent on node size and the likelihood of other causes of increased uptake such as granulomatous disease. A meta-analysis of node siz e in FDG-PET has shown a 5% likelihood of maligancy for nodes measuring 10 \200\22315mm on CT when PET negative, and a 21% likelihood for nodes measuring >16mm. False positive scanni ng is dependent on the underlying prevalence of granulomatous disease. The ranges of report ed sensitivity and specificity are 61% \200\22386% and 73% \200\22396%. Clinical utility in thoracic disease 1 Investigating the solitary pulmonary nodule. 2 Stagi ng lung cancer. 3 Assessing treatment response in lung cancer. 4 Staging and assessing trea tment response in mesothelioma. CHAPTER 13.6 PET-CT 301 Detection of distant metastases: Several studies have shown that PET-CT detects unsus- pect ed metastases in 10 \200\22314% of patients. Adrenal metastatic disease \200\223 PET-CT ap pears of real value in assessing adrenal disease, with a near 100% sensitivity and very hig h, 96% speci \201 city. Bone metastases \200\223 this is in part dependent on correlation with the appearance of the area of FDG activity on CT. If the CT appearances are of metast atic disease, PET has a positive predictive value of 98%, if the CT appearance is not of me tastatic disease PET has a positive predictive value of 61%. Overall PET has a greater sens itivity than 99mTc diphosphonate bone scans. Liver metastases \200\223 PET-CT appears more accurate than CT or US, but may not detect sub 1 cm lesions. Brain metastases are not read ily assessed on conventional FDG-PET due to the high metabolic brain activity. Pleural dise ase \200\223 it appears relatively insensitive, 25%, but of good speci \201 city 90% Prognosis PET-CT appears of value in predicting survival. This may be by assessing the SUV of the primary tumor or by assessing the degree of FDG marrow activity. Fig. 13.6.1 FDG avid left upper lobe tumor (long arrow) with FDG avid left hilar (short arr ow) and aortopulmonary leymphadenopathy (fat arrow). Fig. 13.6.2 FDG avid right hilar tumor (fat arrow) with subtle FDG avid right femoral bone metastasis (thin arrow). F GLEESON 302 Additional abnormalities Up to 5 \200\22310% of all patients undergoing PET-CT have addi- t ional abnormalities such as colonic polyps and thyroid nodules detected. Its main role may be in the early evaluation of patients undergoing chemotherapy, with a re duction in metabolic activity correlating with continued disease response and survival. Fig. 13.6.4 Markedly FDG avid mesothelioma (arrowed) in keeping with sarcomatoid histology and a poor prognosis. Further reading Ceresoli GL, Chiti A, Zucali PA, et al. Early Response Evaluation in Malign ant Pleural Mesothelioma by Positron Emission Tomography with [18F]Fluorodeoxyglucose. J Cl in Oncol 2006; 24: 4587 \200\2234593. Fig. 13.6.3 Small coincidentally detected FDG rectal polyp (arrowed) detected in a patient with lung cancer. De Geus-Oei L, Oyen WJ. Predictive and Prognostic Value of FDG- PET in Nonsmall-Cell Lung C ancer. A Systematic Review Cancer 2007; 119:1654 \200\2231664. Radiation therapy planning PET-CT has been shown to potentially reduce the volume of non-tu mor within the treatment \201 eld, reducing toxicity and potentially allowing an increase in dose to the target tissue De Langen AJ, Raijmakers P, Riphagen I, et al. The size of mediastinal lymph nodes and its relation with metastatic involvement: a meta-analysis. Eur J Cardiothorac Surg 2006; 29: 26 \200\22329. Effectiveness of positron emission tomography in the preoperative assessment of patients wi th suspected non-small-cell-lung can- cer: The PLUS multicentre randomized trial. Lancet 20 02; 359:1388 \200\2231393. 3. Assessment of treatment effect in lung cancer PET has been used post neodadjuvant treatm ent, as an early assessment during chemotherapy and after comple- tion of therapy. A good r esponse and an early response appear to predict survival. Erasmus JJ, Macapinlac HA, Swisher SG. Positron Emission Tomography Imaging in Nonsmall-Cel l Lung Cancer. Cancer 2007; 110: 2155 \200\2232168. Gould MK, Maclean CC, Kuscher WG, et al. Accuracy of Positron Emission Tomography for Diagn osis of Pulmonary Nodules and Mass Lesions: a Meta-analysis. JAMA 2001; 285:914 \200\223924 . 4. Mesothelioma FDG-PET has been shown to be of value in detecting areas of disease suitabl e for biopsy in patients with mesotheli- oma. It is not suf \201 ciently sensitive to be o f value in screen- ing high risk patients, and is not speci \201 c, with false positive sc ans seen post pleurodesis and in patients with other causes of pleural in \202 ammation. I t has been shown to have similar diagnostic accuracy in the detection of mediastinal lympha denopathy as lung cancer. It detects up to an additional 15% distant metastases compared to CT, and should be performed in all patients being assessed for curative surgery. Hellwig D, Graeter TP, Ukena D, et al.18F-FDG PET for Mediastinal Staging of Lung Cancer: W hich SUV Threshold Makes Sense? J Nucl Med 2007; 48:1761 \200\2231765. Truong MT, Marom EM, Erasmus JJ. Preoperative Evaluation of Patients with Malignant Pleural Mesothelioma: Role of Integrated CT-PET Imaging. J Thorac Imaging 2006; 21:146 \200\223153 . This page intentionally left blank M PEAKE RICHARD HUBBORD 304 13.7 Lung cancer screening Background Around 80% of lung cancer patients have locally advanced or metastatic disease b y the time of diagnosis. Although efforts to improve early diagnosis in symptomatic patient s may improve this situation in some patients, it is likely that the bulk of individuals wi th very limited stage disease will only be detected by some form of population-based screen ing. Key elements For a screening test to be accepted it has to succeed in at least three key ar eas: \200 Provide bene \201 t (usually prolong survival) to the individ- uals who are found to have the disease. Confer no signi \201 cant danger to the screened population who do not have t he disease. Should be cost-effective in health economic terms, in other words not impair th e capacity of the health service in providing care for others.