T4 Tumor invading mediastinum, heart, great vessels, trachea, esophagus, vertebra, or carina; or intralobar tumor nodules; or malignant pleural effusion N0 No regional node metastases N1 Ipsilateral peribronchial or hilar node involvement N2 Ipsilateral mediastinal or subcarinal nodes N3 Contra-lateral mediastinal nodes; scalene; or supraclavicular nodes Stage grouping I T1 \200\2232 N0 II T1 \200\2232 N1; or T3 N0 IIIa T1 \200\2232 N2; or T3 N1 \200\2232 IIIb T4 any N M0; or any N3 M0 IV Any M1 OHO-16(259-294) 11/18/02 8:16 AM Page 266 THORACIC CANCER 266 Pulmonary function tests are essential \200\224as well as demonstrating adequate respirator y reserve they are useful in post-operative management. Other investigations include hemato logical and biochemical screening to exclude signi \201cant co-morbidity and electrocardio gram, with or without an exercise test. OHO-16(259-294) 11/18/02 8:16 AM Page 267 This page intentionally left blank OHO-16(259-294) 11/18/02 8:16 AM Page 268 THORACIC CANCER 268 NSCLC \200\224surgery Thoracotomy and major lung resection continue to carry signi \201cant morbidity and mortal ity. Surgery for lung cancer should be carried out in a unit with the appropriate level of experience and expertise. Unnecessary delay may result in a previously operable lung tumor becoming inoperable by progression of disease. In the majority of patients, general anesthe sia with use of double lumen endotracheal tube is desirable to allow one-lung anesthesia du ring thoracotomy. Surgical resection The essential procedures involved include: (cid:2) Lobectomy (cid:2) Bi- lobectomy (cid:2) Pneumonectomy Segmental or wedge resection is generally not advisable because of the risk of incomplete r esection due to the presence of satellite tumor foci within the surrounding lung. In a few patients with poor lung function, segmental or wedge resection may be appropriate. In addition to the removal of all primary tumor with clear mar- gins, regional lymph node s ampling is essential to guide the planning of any adjuvant therapy. In cases where histolog ical proof of malig- nancy is not available pre-operatively, every effort should be made to obtain histology at operation by frozen section before resection is undertaken. In a minority of cases where the tumor is sited at the origin of the upper lobe bronchus, a nd is essentially con \201ned to it, an upper lob- ectomy with sleeve resection of the mai n bronchus, followed by recon- struction by end-to-end anastomosis, will be possible, thus preserving the remainder of functioning lung. Involvement of the chest wall (T3) or pericardium, including the phrenic nerve, in the abse nce of signi \201cant mediastinal lymph node involvement, does not necessarily constitute inoperability. Resection of the involved chest wall should be considered. A signi \201cant portion of pericardium can be removed en bloc in patients with pericardial involvement. Si milarly removal of an involved section of the dia- phragm is technically feasible. Post-operative management Patients should be nursed in an intensive care or high-dependency unit with adequate monitoring of: OHO-16(259-294) 11/18/02 8:16 AM Page 269 NSCLC \200\224SURGERY 269 (cid:2) ECG (cid:2) Pulse rate (cid:2) Blood pressure (cid:2) Central venous pressure (cid: 2) Respiratory rate (cid:2) Oxygen saturation Adequate pain control is essential following thoracotomy and can be provided by thoracic epidural anesthesia, intravenous opiates admini stered by patient-controlled analgesia (PCA), intercostal nerve block prior to wound closur e, or opiates administered by intermittent intra-muscular injection. Oxygen therapy is required in the early post-operative stage, pre- ferably through a nebuli zer, and in patients with signi \201cant airways \200\231 obstruction, a bronchodilator sh ould be added. Regular chest physio- therapy is essential. Post-operative complications Early (within days) (cid:2) Hemorrhage (particularly when there has been widespread pleural adhesions) that may result in a substantial haemothorax (cid:2) Respiratory failure due to drug-induced respir atory depression, pneumothorax with or without surgical emphysema, and retained bronchial s ecretions leading to signi \201cant atelectasis (cid:2) Prolonged air leak following lobectomy (cid:2) Cardiac arrhythmias, particularly at rial \201brillation (cid:2) Chest infection (cid:2) Wound infection (cid:2) Broncho-pleur al \201stula (particularly on the right following pneumonectomy) (cid:2) Empyema Late (within weeks to months) (cid:2) Post-thoracotomy pain (cid:2) Late broncho-pleural \201stula with empyema (cid:2) Tumor recurrence Results of lung resection Post-operative mortality rate should be less than 3% following lo bec- tomy and less than 5% following pneumonectomy. Five-year survival is in \202uenced by a number of factors, the most important of which is pathological staging, post-resection ( see Table 16.2). Overall \201ve-year OHO-16(259-294) 11/18/02 8:16 AM Page 270 THORACIC CANCER 270 Table 16.2 Five-year survival by stage Stage Five-year survival I 60 \200\22380% II 25 \200\22340% IIIa 10 \200\22330% IIIb and IV <5% survival for patients undergoing resection may be as high as 40%, approaching 70% in cases without nodal involvement (N0). However, when mediastinal nodes are involved (N2) only 15% of patients will survive \201ve years. OHO-16(259-294) 11/18/02 8:16 AM Page 271 NSCLC \200\224SURGERY 271 OHO-16(259-294) 11/18/02 8:16 AM Page 272 THORACIC CANCER 272 NSCLC \200\224radiation therapy Introduction Radical radiotherapy is indicated for patients with stage I \200\223II NSCLC w ho are un \201t for surgery, or have good performance status and stage III disease which c an be encompassed in a radical volume. Patients with inoperable non-small cell lung cancer (NSCLC) have a 20 \200\22330% chance of surviving two years if \201t for radical radiotherapy and a similar chance of surviving one year if not. No randomized trial has examined the role of radical radiotherapy in these outcomes. Dose and fractionation The standard international dose is 60 Gy in 30 fractions over 6 week s. Attempts to increase dose by hyperfractionation without acceleration have not shown any bene \201t. CHART, delivering 54 Gy in 36 fractions over 12 days has afforded a 9% surviva l advantage at two years com- pared with standard therapy. No trial has compared these regi mes with shorter 3 \200\2234 week schedules (e.g. 50 \200\22355 Gy in 20 fractions), which remain popular in the UK. CHART is logistically dif \201cult to deliver because of weekend treat- ment; its modi \201cation to exclude weekends, CHARTWEL, delivers 60 Gy in 40 fractions over 17 days. Modi \201cation has not yet been compared to other schedules. Treatment volume No randomized trials have examined what volume should be irradiated. The s tandard in most of the world is the primary tumor and hilar and mediastinal lymph nodes, wi th a 1 \200\2232 cm margin. Retrospective compar- isons have not demonstrated any advantage over volumes encompassing tumor and involved lymph nodes only. In dose escalation studies with conformal therapy, adjuvant nodal irradiation constrains the radiation dose delivered to the primary tumor. Omitting uninvolved nodal groups does not appear to increase local re lapse rate. Chemo-radiation The Non-Small Cell Lung Cancer Collaborative Group (1995)1 over- view sugge sted a 2% increase in 5-year survival when cisplatin-based chemotherapy is added to radical radiotherapy. The RTOG 88-08 study reinforces these conclusions, with a 4-year survival ad vantage of 5% with combined therapy. Chemotherapy delivered synchronously with radiotherapy has not yet been shown to increase s urvival in randomized trials and certainly OHO-16(259-294) 11/18/02 8:16 AM Page 273 NSCLC \200\224RADIATION THERAPY 273 adds to toxicity. A recent review of the RTOG database reported a signi \201cant increase in morbidity in combined regimes. Over one- third of patients receiving chemotherapy and hy perfractionated radiotherapy experienced severe oesophagitis. Future developments Even with CHART, long-term local control is poor. Dose escalation with conformal therapy is being explored to improve this. Using normal tissue complication proba bilities to estimate a \200\230safe \200\231 dose of radiotherapy, up to 92.4 Gy has been delivered to small volumes without signi \201cant morbidity. Post-operative radiotherapy A meta-analysis of randomized trials of post-operative radiothe rapy for completely resected NSCLC has shown impaired survival follow- ing irradiation in p atients with N0 and N1 disease. There is evidence that radiotherapy affords an improvement in local control for patients with N2 disease. The best results have been reported in an Am erican trial delivering 50 Gy in 25 daily fractions. Palliative radiotherapy For many patients with advanced NSCLC, radiation therapy is a key c omponent in symptomatic treatment. Palliative radiotherapy is effective for: (cid:2) Haemop tysis (cid:2) Chest pain (cid:2) Dyspnoea (cid:2) Cough Radiotherapy can also ameliorate sy stemic symptoms such as ano- rexia and weight loss. MRC trials have shown equivalent survival and symptom control for 1-, 2-, and 10-fraction r egimes, establishing the shorter courses as the treatment of choice for symptom control in advanced NSCLC. However, these short schedules are associated with pain and \202u-like sy mptoms in up to 40% of patients. A transient reduction in peak expiratory \202ow rates ma y occur. Most patients receiving two fractions suffer moderate to severe oesophagitis. A third MRC trial suggested that higher-dose palliative therapy (39 Gy in 13 daily fraction s) did offer modest survival advantage for good performance status patients with large tumo rs; comparable to that seen with cisplatin-based combination chemotherapy. OHO-16(259-294) 11/18/02 8:16 AM Page 274 THORACIC CANCER 274 NSCLC \200\224chemotherapy Introduction Initial studies with alkylating agents in advanced NSCLC showed decreased surv ival with chemotherapy, and until recently no agents were available with objective response rates in excess of 20%. UK clinicians \200\231 attitudes to chemotherapy for NSCLC have re mained nega- tive, despite now wide acceptance of such treatment for small cell lung carcin oma. Recent developments indicate pessimism is misplaced. Metastatic disease Tumor response and survival It is now established that cisplatin-based therapy signi \201c antly improves survival and quality of life. In the UK, the most studied regimen is MIC (mi tomycin C, ifosfamide, and cisplatin)) which, when compared with best supportive care, has been shown to improve medi- an survival (by 2 months), 1-year survival (from 18% to 28%), and quality of life. New drugs have emerged with enhanced activity in NSCLC as single agents and in combination with carboplatin or cisplatin. The majority of combination regimens have yet to be tested i n randomized Phase III studies, though paclitaxel/cisplatin proved superior to standard the rapy in terms of tolerability and improvement in quality of life in an EORTC trial, and had a signi \201cantly superior 2-year survival (14.1% v. 11.3%) in an Eastern Co-operative O ncology Group study. In a Phase III study by the South Western Oncology Group, response rat e and 1-year survival were improved when vinorelbine was added Table 16.3 New agents for NSCLC \200 Drug Patient no. 1-year survival (%) Median survival Response rate (%) (Weeks) Vinorelbine 621 20 32.5 24 Gemcitabine 572 21 40.6 39 Paclitaxel 317 26 37.3 41 Docetaxel 300 26 41 52 Topotecan 119 13 38 35 RR = response rate; MS = median survival \200 From Bunn, P.A Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and f uture directions. Clin Cancer Res5, 1087 \200\223100. OHO-16(259-294) 11/18/02 8:16 AM Page 275 NSCLC \200\224CHEMOTHERAPY 275 Table 16.4 New platinum-based combination therapies for NSCLC \200 Drug combination Patient nos. RR (Weeks) MS (%) 1-year survival (%) Paclitaxel + C 333 46 38 40 Vinorelbine + P 328 41 38 35 \200\22340 Paclitaxel + P 286 42 42 36 Docetaxel + P 255 35 35 58 Gemcitabine + P 245 47 57 61 Topotecan + P 22 22 32 26 P = cisplatin; C = carboplatin; RR = response rate; MS = median survival \200 From Bunn, P.A. Jr and Kelly, K. (1998) New chemotherapeutic agents prolong survival and improve quality of life in non-small cell lung cancer: a review of the literature and future directions. Clin Cancer Res5, 1087 \200\223100. to cisplatin. A large, ongoing American study is making direct com- parison in advanced NSC LC of platinum complexes in combination with taxol, gemcitabine, or vinorelbine. Quality of life Although established cytotoxic regimens provide objective tumor response ra tes of the order of 20 \200\22330% in advanced NSCLC, symp- tomatic improvement can be achi eved in a greater proportion of patients: (cid:2) Cough, haemoptysis, and pain are relieved in 70% (cid:2) Anorexia in 40% (cid:2) Dyspnoea in 30% Despite this, use of chemotherapy i n this setting is limited in UK, and it has been questioned whether the cost of non-surgica l treatment for NSCLC (both \201nancial and in terms of treatment-related toxicity) can b e justi \201ed. However, a Canadian health economic analysis suggests that the cost of gai ning a year of life for these patients is between $500 and $7000 \200\224small compared wit h $30 000 basic cost of diagnosis and supportive and terminal care. Stage III disease (cid:2) 33% of NSCLC present in Stage III (cid:2) Trials dif \201cult to interpret (cid:2) Combination chemotherapy and radiotherapy gives better survival than radiotherapy alone in unresectable disease \200\2243-year survival, 13 \200\22323% v. 6% (cid:2) Poor performance status patients do badly with chemotherapy OHO-16(259-294) 11/18/02 8:16 AM Page 276 THORACIC CANCER 276 Cisplatin, and some of the new drugs like gemcitabine and the taxanes, are potent radiosens itizers and there is interest in concomi- tant delivery of chemotherapy and radiotherapy to take advantage of potential synergy. As in SCLC there is evidence that concurrent radio- t herapy may be more effective than sequential, but toxicity remains a problem and an optimum chemotherapy regimen and fractionation schedule for radiotherapy is yet to be determined. Where Stage III disease is technically resectable (Stage IIIA disease, where only ipsilater al mediastinal nodes are involved) surgery cures less than 10% of patients, because of a co mbination of unresected loco-regional disease and occult systemic disease. Chemotherapy imp roves survival over surgery alone, but timing of this remains to be de \201ned. Several sm all studies have suggested a survival advantage for pre-operative or neo-adjuvant chemother apy (with or without radio- therapy) in Stage III disease. Five-year survival rates up to 4 0% have been reported, but this has been achieved in small, selected groups of patients. Tw o recent randomized studies have shown signi \201cantly improved relapse-free and overall survival for patients given cisplatin- based treatment before and after surgery. Overall, the data are not dissimilar from that seen with chemo- therapy followed by radioth erapy in unresectable disease, and it is not clear if surgery has a role in this situation. On the other hand, only 5 \200\22315% of patients undergoing neo-adjuvant therapy have a p atho- logical complete response at surgery, demonstrating the importance of further local t reatment if cure is the aim. Large Phase III trials of chemo-radiotherapy pre-surgery (Inte rgroup) and of chemothera- py followed by radiotherapy or surgery (EORTC) are in progress t o help clarify this issue. Other groups are testing ef \201cacy of newer drug combinations in this setting. Adjuvant therapy Meta-analysis of adjuvant chemotherapy trials in NSCLC has shown a 5% impr ovement in 5-year survival for patients treated with a cisplatin-based regimen after surgic al resection. This bene \201t held for patients across Stages IB \200\223IIIA. Such treatm ent has not however been widely adopted in the UK. While neo-adjuvant strategies offer potential downstaging of disease, increasing the likeli hood of a complete resection and theoret- ical reduction in risk of tumor dissemination at surgery, no studies have yet shown pre-operative chemotherapy to be superior to post- opera tive adjuvant therapy. Conclusion Chemotherapy for inoperable NSCLC offers bene \201ts similar to those obtained with chemotherapy in SCLC in terms of survival. Results of adjuvant treatment also suggest that a survival bene \201t comparable to OHO-16(259-294) 11/18/02 8:16 AM Page 277 NSCLC \200\224CHEMOTHERAPY 277 that observed in breast and colorectal cancer can be achieved. Grounds for the current nihi listic view of NSCLC chemotherapy are diminishing, but patients still need to be entered in to clinical trials wherever possible in order better to re \201ne current approaches. OHO-16(259-294) 11/18/02 8:16 AM Page 278 THORACIC CANCER 278 Small cell lung cancer \200\224 radiotherapy Background Patients with small cell lung cancer (SCLC) are usually treated by primary chemo therapy because of its chemo-responsiveness and fre- quent dissemination at time of diagnos is. SCLC is, however, also the most radio-responsive variety of bronchial carcinoma and rad io- therapy has an important role in its management. In patients with a localized tumor, th oracic irradiation (TI) and prophylactic cranial irradiation (PCI) improve disease control at these sites and lead to prolongation of survival when compared to chemotherapy alone. In addition, radiotherapy is a useful palliative treatment for patients relapsing after, resi stant to, or refusing chemotherapy. Thoracic irradiation (TI) (cid:2) 60% of relapses after chemotherapy are in the thorax (cid:2) TI reduces risk by 50% and improves survival (cid:2) Survival improves from 9 to 14% at 3 years (cid:2) Schedule is uncertain (cid:2) Early and concurrent with chemotherapy \200\224best results but more side-effects Prophylactic cranial irradiation (PCI) (cid:2) SCLC has propensity for brain metastases (cid:2) 20% have brain involvement at diag nosis (cid:2) 80% have brain involvement at death (cid:2) Blood \200\223brain barrier limit s effectiveness of chemotherapy (sanc- tuary site) (cid:2) Median survival once CNS disease develops is 3 months; 50% only have reasonable pal liation with chemotherapy or radiotherapy (cid:2) Low-dose PCI halves risk of brain metastases (cid:2) Low-dose PCI \200\224small imp rovement in survival (cid:2) Dose and schedule of PCI is uncertain (cid:2) Not given concur rently with chemotherapy Palliative radiotherapy A short course of irradiation to either the primary tumor or the si te of metastases can provide useful symptom control. The choice of dose OHO-16(259-294) 11/18/02 8:16 AM Page 279 SMALL CELL LUNG CANCER \200\224RADIOTHERAPY 279 and radiation schedule is similar to that used in NSCLC and should follow the basic princip les of using the lowest effective dose with minimal additional toxicity. In most situations a single fraction or up to \201ve fractions of treatment will suf \201ce. Radiotherapy administration Decisions about use of combined modality treatment for individu al patients are based on assessment of their prognostic factors. This approach brings incre ased risks of toxicity and overall demands on patients and should be reserved for those wit h a realistic prospect of long-term survival. Exact timing of administration, dose, and fra c- tionation schedule of TI and PCI will be determined by individual protocols and may be s ubject of study in a randomized clinical trial. Hyperfractionated schedules and concurrent administration of chemotherapy and irradiation remain investigational. For routine use outs ide clinical trials, the following are commonly used: TI \200\22450 Gy in 2 Gy daily fractions or biological equivalent PCI \200\22424 Gy in 8 fr actions, 30 Gy in 10 fractions, or 36 Gy in 18 fractions Treatment volume of TI will depend on time of administration and on local practice. It is c ommon practice to irradiate the mediastinum even in the absence of lymphadenopathy because of frequency of occult nodal metastases. Pre-chemotherapy CT and chest radiographs are important to ensure that pre-chemotherapy sit es of disease are encompassed by radiotherapy \201elds. Mega-voltage irradiation is used and sophis- ticated approaches to \201eld placement and dosimetry are necessary to ensure optimal trade-off between preserving spinal cord tolerance and minimizing radiation dose t o the surrounding normal lung. This often means a \200\230shrinking \201eld \200\231 or phased approach. For PCI planning it is important to encompass all meningeal surfaces, particularly the cribriform plate and middle cranial fossa. Follow-up This is designed to detect recurrences and monitor side-effects of treat- ment. T reatment of recurrent disease is always palliative in intent. Late effects of TI on lung an d PCI on cognitive function are important limitations and need to be formally assessed by t he team responsible for administration of radiotherapy. Follow-up chest radiographs will sh ow mediastinal \201brosis in all patients. Associated functional impact depends on volume , previous respiratory reserve, and patients \200\231 activity levels. Mediastinal \201brosis makes interpretation of follow-up radiology dif \201cult and may lead to concerns about recurrence that can only be resolved by sequential radiology. Thorac ic CT gives better de \201nition of cross-sectional anatomy, but still needs to demonstrat e a change to reliably con \201rm recurrence. OHO-16(259-294) 11/18/02 8:16 AM Page 280 THORACIC CANCER 280 Following PCI about 30% of patients will develop \200\230somnolence \200\231 as a classica l, self-limiting effect, 2 \200\2233 months after treatment. With longer follow-up patients may complain of recent memory loss, but formal neuropsychometric evaluations have failed t o demonstrate signi \201cant deterioration attributable to PCI. Future research The question of optimal scheduling of TI needs to be resolved. Current evid ence suggests early introduction may be more effective than traditional consolidation thera py. This approach may not be suitable for patients with bulky mediastinal disease or with t umor involvement outwith a safe size of radiation \201eld. Further research needs to addr ess the use of hyperfractionated or accelerated radiation techniques and use with concurren t chemotherapy. Similar uncertain- ties exist for radiation timing, dose, and optimal sched ules of PCI. OHO-16(259-294) 11/18/02 8:16 AM Page 281 SMALL CELL LUNG CANCER \200\224RADIOTHERAPY 281 OHO-16(259-294) 11/18/02 8:16 AM Page 282 THORACIC CANCER 282 SCLC \200\224chemotherapy Introduction SCLC accounts for 16 \200\22320% of all lung cancers and its incidence is risi ng in the developed world, particularly in women. It is a rapidly growing tumor that is now recognized as a systemic disease making surgery inappropriate for the vast majority of pat ients. Prior to the introduction of systemic treatment with chemotherapy in the 1970s, the outlook for patients diagnosed with this disease was dreadful, with a median survival of six weeks for patients with extensive disease and three months for those with limited disease. Combi nation chemotherapy is now the standard treatment for both categories of disease. Overall survival has been extended signi \201cantly in recent years \200\224 5 \200\22310% of selected patients with limited disease can survive long term. Unfortunately, the vast m ajority of patients die of their disease, and patients with extensive disease only have a m edian survival of 7 \200\22311 months. Staging and prognostic factors A much simpli \201ed staging system is used for SCLC as the vast majority of patients are initially treated with chemotherapy irrespec- tive of diseas e extent. A two-stage system was drawn up by the Veterans Administration Lung Group: (cid:2 ) Limited-stage disease: tumor con \201ned to one hemithorax and regional nodes that may b e encompassed within tolerable radiation therapy \201elds. (cid:2) Extensive-stage disease: disease beyond these bounds. Within these broad categories , subgroups may be de \201ned according to one or more of the following prognostic factors : (cid:2) Performance status (cid:2) Sex (females fare better) (cid:2) LDH (cid:2) Alkaline phosphatase (cid:2) Hyponatraemia A number of drugs have been found to have activity as si ngle agents and a variety of combination regimens have been developed (see Table). CAV and EP have similar ef \201cacy. EP causes more nausea and vomiting but less myelosuppression, neurotoxicity, and cardiac toxicity. The substitution of ifosfamide for EP has shown a mod est improvement in survival in extensive disease. OHO-16(259-294) 11/18/02 8:16 AM Page 283 SCLC \200\224CHEMOTHERAPY 283 Table 16.5 Commonly used combination regimens in SCLC 115 mg/m2 i.v. days 3 \200\2235 q. 3 weeks EP Etoposide 60 \200\22380 mg/m2 i.v. day 1 q. 3 weeks Cisplatin 50 mg/m2 i.v. days 1 \200\2235 q. 3 weeks CAE Etoposide 45 mg/m2 i.v. day 1 q. 3 weeks Doxorubicin 1000 mg/m2 i.v. day 1 q. 3 weeks Cyclophosphamide 1000 mg/m2 i.v. day 1 q. 3 weeks CAV Cyclophosphamide 50 mg/m2 i.v. day 1 q. 3 weeks Doxorubicin 2 mg/m2 i.v. day 1 q. 3 weeks Vincristine These combination regimens produce response rates of over 80%, with complete responses in 3 0 \200\22340% of patients with limited disease and 10 \200\22320% with extensive disease. M any patients with SCLC are elderly, with co-morbid conditions, and it was hoped that single -agent oral etoposide would be effective and better tolerated by this group. However, in tw o randomized trials oral etoposide was found to be detrimental to quality of life and less effective than the standard regimens. Chemotherapy alone is not entirely responsible for improvement in survival, with developmen ts in thoracic and cranial irradiation taking place in tandem. The wide range in survival r ates between different clinical trials can be explained in part by differences in selection criteria. Intrinsic and emergent drug resistance are thought to under- lie ultimate treatm ent failure in SCLC and a number of strategies have been investigated in an attempt to over come this. Alternating chemotherapy regimens Goldie et al.2 proposed a hypothesis, based on a mathemat ical model, that drug resistance could be overcome by using alternating regimens, provided that each regimen was capable of producing high rates of complete remission and that the tw o regimens were not cross-reactive. However, several trials have failed to show clinically signi \201cant improvement in survival with this approach. Dose intensi \201cation This can be achieved by decreasing the interval between treatments or by increasing the dose at each treatment. Modest increases in the doses of CAV and EP r egimens have been achieved but failed because of increasing hematological toxicity. An impr ovement in median sur- vival was found in patients with limited stage disease when a com- b ination of ifosfamide, carboplatin, etpoposide, and vincristine was given in a three-weekly compared to a four-weekly schedule. If there is a role for dose intensi \201cation it is likely to be in patients with limited disease. Failure to achieve planned dose intensi \201cation as OHO-16(259-294) 11/18/02 8:16 AM Page 284 THORACIC CANCER 284 a result of toxicity may actually result in shorter survival for patients in the intensi \201ed arm. The addition of colony-stimulating factors to facilitate dose escala- tion has been shown t o decrease hematological toxicity in some trials but not to affect survival. Their routine use is not therefore currently recommended. High-dose therapy with autologous haemopoietic cell support has again failed to show an increase in survival and currently is not recommen ded for use outwith a clinical trial. Maintenance chemotherapy It was postulated that extending the period of chemotherapy might delay relapse. Several trials have assessed the bene \201t of following standard induction treatment with maintenance chemotherapy. Overall, though they have shown longer times to p rogression with maintenance treatment, there has been little impact on survival. Biological therapies are always more likely to be effective in cancer patients with a low t umor burden, and for this reason their use has been explored in patients with SCLC in compl ete remission following standard treatment. However, trials of maintenance interferon in su ch patients have failed to show any survival advantage. New drug development The demonstration of activity with novel chemotherapeutic drugs in SCL C is dif \201cult since most patients with the disease will have received \201rst-line c hemotherapy, and there is a danger that active agents may be dismissed because they fail to show activity as second-line agents. However, it has been observed that patients relapsing longer than three months from the completion of chemotherapy have a much greater chance of responding to the same treatment, suggesting con- tinued drug sensitivity. Patients in thi s clinical situation are appro- priate candidates to receive investigational combinations. Similarly, patients who relapse within three months, and who are, therefore, thought to hav e disease refractory to conventional therapy, test non- cross-resistant drugs with novel mo des of action. Docetaxel, paclitaxel, topotecan, irinotecan, and gemcitabine have all been found to be act ive in SCLC. Whether they are incorporated into standard regimens will depend on a number o f factors including toxicity, cost-effectiveness, and the demonstration of non-cross- resis tance with current standard drug. Other novel treatments under development include: (cid:2) Drugs interfering with autocrine growth-factor loops (cid:2) Matrix metalloproteinase inhi bitors (cid:2) Anti-angiogenic factors (cid:2) Gene transfection approaches OHO-16(259-294) 11/18/02 8:16 AM Page 285 SCLC \200\224CHEMOTHERAPY 285 OHO-16(259-294) 11/18/02 8:16 AM Page 286 THORACIC CANCER 286 Mesothelioma Epidemiology and incidence Malignant pleural mesothelioma (MPM) is an aggressive tumor aris ing from the serosal lining of the chest and abdomen with survival rates of less than one y ear reported following diagnosis. (cid:2) Rare \200\2243000 cases per year in UK; the incid ence is expected to rise over the next decade before peaking (cid:2) Age \200\22460 \200\22370 years (cid:2) Male:female ratio, 5:1 (cid:2) Caused by as bestos exposure (cid:2) Other causative agents include \200\224 radiation \200\224 thorium dioxide \200\224 silicate \201bres \200\224 Simian Virus 40 (SV40), d is- covered as a contaminant of early poliovirus vaccines Pathology Mesothelioma may present as a benign or malignant process. Benign mesothelioma us ually presents as an asymptomatic solitary mass and is not typically associated with asbest os exposure. Malignant tumors may be localized or diffuse and are more commonly associated with asbestos exposure and symptoms such as chest pain and dyspnoea. Three distinct maligna nt subtypes have been identi \201ed microscopically: (cid:2) Epithelial (approx. 50% of al l cases) (cid:2) Sarcomatous (cid:2) Mixed histologies Distinguishing mesothelioma from oth er intra-thoracic malignancies such as adenocarcinoma, requires the assistance of an experi enced pathologist. Frequently, light microscopy and standard histochemical stains are inade quate alone. Therefore pathologists use techniques such as electron microscopy and immunohi stochemistry to facilitate this distinction. Clinical and radiological presentation Mesothelioma can be insidious in its onset with a me dian time from \201rst symptoms to diagnosis of 2 \200\2233 months. Symptoms at presentat ion commonly include non-pleuritic chest pain and dyspnoea. Con- stitutional symptoms such as fever, fatigue, and weight loss are seen in OHO-16(259-294) 11/18/02 8:16 AM Page 287 MESOTHELIOMA 287 30% of patients. Physical examination frequently demonstrates decreased breath sounds and d ullness to percussion due to a pleural effusion or diffuse pleural tumor. Signs of advanced disease are: (cid:2) Chest wall mass (cid:2) Hoarseness (cid:2) Superior vena cava syndrom e (cid:2) Horner \200\231s syndrome (cid:2) Ascites \200\224heralding abdominal involvement (cid:2) Lymphadenopathy \200\224an infrequent \201nding Laboratory results in mesothelio ma are usually unremarkable with no serological tumor marker reproducibly isolated. The rad iological presentation of mesothelioma is non-speci \201c. Pleural effusion is com- mon an d may be associated with pleural thickening and nodularity. The extent of the pleural mass and encasement of the lung is well demonstarted by CT. However, this imaging modality is le ss sensitive in detecting mediastinal or transdiaphragmatic involvement. Magnetic resonance imaging (MRI) of the chest and upper abdomen provides superior de \201n ition of tissue planes, in addition to sagittal and coronal views of the diaphragm and thor ax apices, and is an important adjunct to staging. Diagnosis Thoracoscopy remains the procedure of choice to obtain a patho- logical diagnosis of malignant mesothelioma, with an 80% diagnostic yield. Thoracocentesis and percutaneous pleural biopsy has a yield of only 30 \200\22340%. When thoracoscopy is not possible due to obliteration of the pleural space by the tumor, an open pleural biopsy may be per- formed. Careful planning of the incision site is essential because mesothelioma has a propensity t o implant within chest wall wounds. Exploratory thoracotomy should be avoided. Table 16.6 Brigham Staging System for malignant pleural mesothelioma Stage Description I Disease completely resected within the capsule of the parietal pleura without adenopathy; ipsilateral pleura, lung, pericardium, diaphragm, or ch est wall disease limited to previous biopsy sites II All of Stage I with positive resection margins and/or intrapleural adenopathy III Local extension of disease into the chest wall or mediastinum, heart, or through diaphragm into peritoneum; or with extrapleural lymph node involvement IV Distant metastatic disease OHO-16(259-294) 11/18/02 8:16 AM Page 288 THORACIC CANCER 288 Staging In 1976, Butchart proposed a staging system based on the extent of tumor involvemen t within the chest, but this system correlated poor- ly with survival. Subsequently, altern ative staging systems have been proposed, several based on a TNM concept, although none hav e gained universal acceptance. The Brigham staging system provides a straightforward characteri- zation method, based on k ey disease characteristics, that strati \201es survival. In a series of 183 patients treat ed in a multimodality setting, median survival for patients with stage I, II, and III disea se was 25, 20, and 16 months respectively. Accurate pre-operative pathological staging is best achieved by thoracoscopy for pleural ev aluation, mediastinoscopy for mediastinal nodal involvement, and laparoscopy to rule out pe ritoneal seeding or diaphragmatic involvement when indicated. Treatment Without treatment, the average patient with MPM survives less than one year from the time of diagnosis. As a result of this poor prognosis various therapeutic options have been explored includ- ing: (cid:2) Radiotherapy (cid:2) Chemotherapy Immunotherapy (cid:2) (cid:2) Surgery Individually, each of these modalities has been disappointing when compared to single-modality treatment results. Current experience has shown multimodality therapy t o offer improved survival in selected patient groups. Multimodality therapy should be carri ed out in the context of an approved study protocol by thoracic surgeons experienced in tre ating this disease. At Brigham and Women \200\231s Hospital, Boston, extrapleural pneumon- ectomy followed by c hemotherapy (carboplatin and paclitaxel) and radiotherapy (40.5 Gy) is being used. Recently , 183 patients have been reviewed, demonstrating an overall median survival of 17 months an d 2- and 5-year survival rates of 36% and 14% respectively. Positive predictors for improve d outcome were epithelial histology, negative resection margins after operation, and negati ve extrapleural nodal status. Patients with all three positive predictors enjoyed a 51-mont h median survival with 2- and 5-year survival rates of 68% and 46% respectively. The following novel therapeutic approaches are currently under- going active clinical inves tigation in an effort to improve treatment survival outcome: OHO-16(259-294) 11/18/02 8:16 AM Page 289 MESOTHELIOMA 289 Intracavitary, hyperthermic chemotherapy (cid:2) (cid:2) Gene therapy Immunotherapy (cid:2) (cid:2) Photodynamic therapy OHO-16(259-294) 11/18/02 8:16 AM Page 290 THORACIC CANCER 290 Thymic tumors Introduction Tumors derived from the thymus (thymomas) comprise approxi- mately 20% of all mediastinal tumors and are the most common tumor in the anterior mediastinum. Thymomas occu r at any age but are rare before the age of 20 and peak between 40 \200\22360 years. The in cid- ence varies somewhat in different countries with high values in the Far East. The aver age in Europe is around 0.5 new cases per year per 100 000. Etiology of these tumors is unk nown; a possible relation to Epstein \200\223Barr virus infection has not been proven. Pathology Most thymomas are slow-growing \200\230low-grade \200\231 malignant tumors. It i s believed that they derive from epithelial elements, but the tumors retain the capacity fo r production of T cells. The T cells are generally of normal phenotype. According to the re lative abundance of epithe- lial and lymphocytic cells, histological subgroups have been de scribed: (cid:2) Epithelial (cid:2) Lymphocytic (cid:2) Mixed or lympho-epithelial type The se cellular characteristics have no clear in \202uence on prognosis. In contrast, the gros s appearance of the tumor is related to clinical prognosis. The presence or absence of an i ntact capsule is of prognos- tic importance and local invasiveness remains the most consist ent factor in predicting outcome. The metastatic potential of thymomas is dif \201cult to assess on the basis of histology and cytological features. A \200\230benign \200\231 thymoma has been de \201ned as a tumor that is well encap- sula ted and does not invade adjacent mediastinal structures; 50 \200\22365% of thymomas \201t this de \201nition. The differentiation between benign and malignant thymoma is, however, dif \201cult and thymomas should in general be regarded as potentially malignant. In all cases where residual tumor is left after surgery, adjuvant therapy should be considered. Presentation and clinical features (cid:2) 30% \200\224no local symptoms (cid:2) Produce paraneoplastic syndromes (cid:2) 70% associated with an immunological phenomenon OHO-16(259-294) 11/18/02 8:16 AM Page 291 THYMIC tumors 291