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Pieter E Postmus
Head of Department
Department of Pulmonology
VU University Medical Center
Of all malignancies, lung cancer is by far the most frequent cause of death. Of all patients diagnosed, only around 10–15% will still be alive five years after diagnosis. By far the most important cause of lung cancer is the use of tobacco products, and despite extensive efforts, approximately 30% of the population are still smoking.
Within the heterogeneous group of tumours called lung cancer, several different histological types have to be distinguished. The absolute frequency of the different histological types has also been changing during the last two decades;(1) the incidence of smallcell lung cancer is lower, whereas adenocarcinoma is becoming the most frequent type(2) and squamous cell lung cancer is slowly becoming less frequent. The rising incidence of malignant mesothelioma is also a matter of concern.(3)
Lung cancer staging
Although the two lung cancer staging systems currently used are far from perfect, they can be used for prognostic and subsequently develop guidelines. The system for small-cell lung cancer (SCLC) includes two stages that are distinguished and used for decisions on treatment. The second system, for nonsmall-cell lung cancer (NSCLC), is based on the widely used TNM classification. For this tumour type, staging is of paramount importance to decide which treatment is most appropriate for a specific patient. In addition, other patient-related factors, such as cardiovascular and pulmonary function, are important.
New staging systems are currently being developed based on data from more than 100,000 patients. For NSCLC, too little is known of the differences of clearly different patients within the same subgroup. For example, stage IA includes all patients with tumours </=3cm in diameter without lymph node metastases, although it is known that tumours </=1cm in diameter have a better prognosis than larger tumours.(4) Stage IIIB is also a very heterogenous group.
Current staging procedures are highly time-consuming, partly due to a lack of radiological equipment such as computed tomography (CT) scanners and magnetic resonance imaging (MRI). Positron emission tomographs (PETs) allow the exclusion of mediastinal lymph node involvement and detection of distant metastases that are still asymptomatic and not detected by other standard staging investigations. If used in the appropriate way, it is of major benefit for treatment decisions, for example in patients considered operable after standard staging procedures.(5)
Treatment of SCLC
First-line chemotherapy consists of etoposide/cisplatin for four cycles; for limited-disease patients, concurrent radiotherapy during the second or third cycle is added. Every patient with a good response to chemotherapy will benefit from prophylactic cranial radiotherapy to eradicate asymptomatic microscopic metastases and hopefully prevent, or at least delay, these metastases becoming symptomatic. Irinotecan might soon be introduced in first-line therapy to replace etoposide. Studies to confirm the initial positive trial from Japan are underway.(6)
Treatment of NSCLC
After staging, a decision has to be made as to which treatment is appropriate. Historically, surgery has been the treatment of choice for patients with adequate cardiopulmonary function without signs of locoregional or distant metastases, stages I and II. For these patients, the aim was cure; however, for the majority of patients (within months or at best a few years), metastases eventually become symptomatic. For these patients, as well as for all other patients who were beyond potential cure by surgery at initially staging, only palliative treatment was available. In a small number of patients, locoregional radiotherapy resulted in prolonged disease-free survival. In general, radiotherapy resulted in a delay in tumour growth but not in cure. Cure could be achieved only in up to 30% of patients in the stage I and II subgroups.
After the publication of a meta-analysis on chemotherapy in stage IIIB and IV patients,(7) the attitude towards chemotherapy changed. Chemotherapy is currently the state-of-the-art in treatment of stage IV and so-called “wet” stage IIIB (carcinomatous pleural effusion), with the exception of patients with a poor performance status. Platinum should be part of the chemotherapy regimen, combined with one of the recently introduced new drugs for the treatment of NSCLC, such as gemcitabine, a taxane derivative, or vinorelbine. Second-line treatment with these cytotoxic drugs has recently been demonstrated to have a beneficial effect.(8) Second-line treatment in patients with progression after first-line therapy should increase in the next few years. Erlotinib, an epidermal growth factor receptor (EGFR) antagonist, has recently been demonstrated as having a positive effect compared with placebo, with both survival and quality of life being improved in the treated group.(9)
Combined modality treatment – chemotherapy and radiotherapy – has become the standard for the treatment of the earlier stages of NSCLC. Whether chemotherapy should be combined with or followed by surgery or radiotherapy in the IIIA subgroup is still an unsolved question. The result of EORTC study 08941 will hopefully give an answer. If chemotherapy combined with radiotherapy becomes the standard for stage IIIA, the standard treatment will be one or two induction chemotherapy cycles, followed by the concurrent administration of standard chemotherapy and radiotherapy. Whether combining chemotherapy, radiotherapy and surgery will become standard in selected cases, such as superior sulcus tumours, is still a matter of research.
Until recently, the standard of care was surgery after careful staging. Unfortunately, in the majority of patients, recurrence of disease will occur (within months to a few years). Results of four recent well-designed large studies have become available. The Italian study was not positive,(10) while the IALT study demonstrated a small but significant benefit for the chemotherapy group.(11) At the 2004 ASCO meeting, a Canadian study revealed a 15% survival difference for the chemotherapy group,(12) and a study of the CALGB in a subgroup (stage IB only) found a difference of 12% after four years.(13) These data were sufficiently convincing, and the administration of postoperative chemotherapy is now considered the standard treatment for completely resected stage IB and II tumours.
Approaches for the treatment of stage IB and II are identical. For stage IA, there are no data to support the use of postoperative chemotherapy. Whether possible differences in approach are possible within this group of small tumours is unclear.(4) Based on the Lung Cancer Study Group randomised trial,(14) a higher local relapse is anticipated after limited resection. However, in this study, the number of real small IA tumours (<1cm) is too small to draw conclusions. This problem becomes relevant with the introduction of early detection programmes, such as low-dose spiral CT and sputum cytology, at a large scale.(15) Using these techniques, very small lesions can be detected. If these lesions are in the central airways it is possible to achieve cure by local endobronchial treatment. In the case of parenchymal lesions, surgery (lobectomy) is the standard, although some studies have demonstrated a high cure rate with limited resections. Another potential promising approach is the use of four-dimensional (4D) radiotherapy,(16) which allows very high-dose radiotherapy on a very small area.
Bronchioloalveolar cell carcinoma
Bronchioloalveolar cell carcinoma (BAC) is a subgroup of adenocarcinoma. This type of tumour is usually bilaterally present in the parenchyma and, thus, inoperable. Studies on EGFR antagonists have shown that a higher sensitivity for these new drugs is probably present within this tumour type.(17) Further research on mutations within the EGFR is needed before it becomes possible to select potentially sensitive tumours.(18)
Research is focusing on specific characteristics of tumours in relation to sensitivity to different cytotoxic agents.(19) The expression of specific genes is related to a different sensitivity for currently used chemotherapeutic drugs.(20) The use of new techniques such as microarrays will have an impact on the choice of specific drugs for specific tumours.
The treatment of this tumour has been extremely difficult and frustrating, as no chemotherapeutic drug or combination was found to impact on survival or result in adequate palliation. The new antimetabolite pemetrexed constitutes an improvement.(21) In addition, results obtained with pemetrexed were to some degree confirmed by the use of another antimetabolite, raltitrexed.(22) When pemetrexed becomes available it will be considered, in combination with cisplatin, as the standard of care for mesothelioma.