Clinical trials have resulted in significant seminal trials which have led to changes in the management of these patients. Those seminal studies in screening, chemoprevention and treatment are outlined.
Three US randomised screening studies failed to detect an impact of screening high-risk patients with chest radiographs or sputum cytology on mortality, although earlier stage cancers were detected in the screened groups.3-5 These studies have been criticised for a number of potential methodological and statistical problems, such as over-diagnosis and analysing data by survival rather than mortality.6
Recently, several clinical studies have demonstrated that early stage lung cancers can be detected with the use of spiral CT that would not have been detected by routine chest X-ray.7 Spiral CT is a CT scan which does not evaluate the mediastinum and thus does not use contrast or require the presence of a radiologist, employs low doses of radiation and can be completed within one patient 'breath'. Because it can be done rapidly and does not require a radiologist to be present, it is being used in some centres to screen for lung cancers in high-risk populations. However, it has not been determined whether there is a survival benefit with this technique.6 7 Given the availability of this scanning technique in the community, it is imperative that clinical trials be completed to determine if the early detection of small tumours results in improved survival that is not a result of lead time or length bias.
Treatment of NSCLC is dependent primarily on stage of disease at the time of diagnosis and stage, in turn, is dependent upon the size of the tumour (T), location of nodal involvement (N), if any, and presence or absence of distant metastases (M). The current TNM staging classification is shown in Table 11.1 and the stage grouping in Table 11.2.
A lobectomy is the treatment of choice for stage I NSCLC, with cure rates of 60-80% reported. Within stage I, patients with T2, N0 disease do not fare as well as those with T1, N0 cancers. In approximately 20% of patients with medical contraindications to surgery but with adequate pulmonary function, high-dose radiotherapy will result in cure. No role of adjuvant chemotherapy for stage I NSCLC has been identified.
Chemoprevention: Patients with a resected stage I NSCLC are at high risk of approximately 1% per year for the development of second lung cancers, prompting a number of ongoing clinical trials looking at the role of chemoprevention. Surprisingly, several randomised studies have demonstrated that the use of vitamin A or one of its derivatives at best, does not prevent lung cancer in smokers and at worst, may increase the risk of developing it.8-10 Preliminary studies have suggested that selenium may reduce the incidence of lung cancer and total cancer mortality. In a multi-centre, double-blind, randomised, placebo-controlled trial, 1312 patients were randomised to receive either selenium or placebo.
The selenium group had fewer total carcinomas, including lung cancer with a relative risk of 0.54 and a 95% confidence interval of (0.30 to 0.98) (p = 0.04).11 This has formed the basis for an intergroup chemoprevention trial which is now ongoing.
Stage II and 'Non-Bulky' IIIA Disease
Treatment of locally advanced NSCLC is one of the most controversial issues in the management of lung cancer. Treatment options include surgery for less-advanced disease, or radiotherapy, either of which has been given with or without chemotherapy for control of micrometas-tases. Interpretation of the results of clinical trials involving patients with locally advanced disease has been clouded by a number of issues, including changing diagnostic techniques, different staging systems and heterogeneous patient populations that may have disease that ranges from 'non-bulky' stage IIIA (clinical N1 nodes, with N2 nodes discovered only at the time of surgery or mediastinoscopy), to 'bulky' N2 nodes (enlarged adenopathy clearly visible on chest X-ray films, or multiple nodal level involvement), to clearly inoperable stage IIIB disease.
Post-operative Thoracic Radiotherapy. The treatment for stage II and selected IIIA NSCLC patients is surgical resection. However, many of these patients will relapse, prompting numerous trials evaluating the role of post-operative radiotherapy or chemotherapy. A meta-analysis examining the role of post-operative radiotherapy (PORT) found that patients randomised to receive PORT actually had an inferior survival to those randomised to observation alone.12 In a meta-analysis of 2128 patients in nine clinical trials of post-operative radiotherapy, a 7% survival decrement from radiation was identified. However, this particular analysis included a number of trials from the 1960s and 1970s when staging was highly inaccurate and relatively outmoded radiation therapy technologies were utilised. In addition, several of the trials included in this report aggressively treated patients with no evidence of nodal involvement or those with early nodal involvement only, a group that by today's standards would not be subjected to postoperative radiation therapy. More recent studies looking at the role of PORT have concluded that PORT does not prolong survival, but does enhance local control. The most comprehensive randomised trial in this regard was performed by the Lung Cancer Study Group and it demonstrated major improvement in intrathoracic disease control.13 For those patients receiving thoracic radiotherapy, the intrathoracic failure rate was only 3%, compared to 43% for patients not receiving post-operative radiotherapy, although no significant survival advantage was identified.
Adjuvant Chemotherapy. Given the propensity of these resected patients to relapse with distant disease, adjuvant post-operative chemotherapy has been of significant interest. A meta-analysis published in 1995 found a small improvement in survival with post-operative adjuvant chemotherapy that borderlined on statistical significance (p = 0.08),14 leading some clinicians to conclude that adjuvant chemotherapy was of benefit. However, a randomised intergroup study has been completed in which patients were randomised to receive either radiotherapy plus chemotherapy (cisplatin and etoposide for four cycles) or radiotherapy alone. The median and long-term survival of the two arms was nearly identical.15 Once again, the fact that the meta-analysis included older studies, in which chemotherapy regimens, staging and other clinical characteristics were different, may account for this discrepancy. Although the role of neoadjuvant chemotherapy is under investigation, it cannot be routinely recommended until the results of randomised clinical trials confirm clinical benefit.
Pre-operative Chemotherapy plus Surgery. There have been two small randomised studies involving surgery with or without pre-operative chemotherapy which popularised this approach. Both involved 60 patients and both report response rates of 35-62% following induction chemotherapy. Both have also reported prolonged survival, prompting early closure of both trials. In the European trial, the median survival time was 26 months for patients receiving pre-operative chemotherapy plus surgery, compared to 8 months for patients treated with surgery alone.16 In the MD Anderson trial, the median survival of the 32 patients randomised to the surgery-alone group was 11 months compared to 64 months in the 28 patients randomised to the combined-modality arm.17 Of note, however, is the fact that updated results of the MD Anderson trial, while still statistically significant, showed a narrowing of the survival curves, with a median survival of 14 months and 21 months for the surgery alone and combined modality arms, respectively.18
A larger trial has recently been reported.19 Three hundred and fifty-five patients with stage I, II or IIIA disease were randomised to three cycles of chemotherapy followed by surgery or to surgery alone. Median survival (37 months vs. 26 months) and 2-year survival (52% vs. 59%) were not statistically different between the two groups. However, a subset analysis in which patients who died within 150 days of perioperative problems were excluded revealed a 0.77 reduction in risk which was statistically significant (p = 0.03). Other subset analysis looked at outcome by patient stage and found that the patients with N0/N1 disease who received chemo/surgery had a hazard ratio of 0.68, compared to patients with N2 disease, where the hazard ratio was 1.04.
Despite the results of the Depierre trial, many clinicians continue to use pre-operative chemotherapy for patients with stage IIIA disease. An intergroup study evaluating chemo/RT vs. chemo/RT surgery has recently been completed; these results are eagerly awaited.
Locally Advanced 'Bulky' Stage IIIA/IIIB Disease
The optimal treatment for bulky stage IIIA and stage IIIB disease is also controversial. Current investigational efforts are directed at identifying the optimal combined-modality approach, involving treatments directed at local control of the disease, i.e., surgery or radiotherapy, and micrometastatic disease, i.e., chemotherapy. Possibilities include radiotherapy only, preoperative chemotherapy, or chemotherapy plus radiotherapy.
Chemotherapy plus Radiation Therapy. Chemotherapy plus radiotherapy is the treatment of choice for patients with bulky or inoperable stage III disease. Two randomised studies have demonstrated an improvement in median and long-term survival with chemotherapy followed by radiation therapy versus radiotherapy alone.20'21 More recently, two randomised trials have shown that concurrent chemoradiotherapy results in prolonged survival, albeit at the expense of enhanced toxicity, compared to sequential treatment.22'23 Other active areas of investigation include choice of chemotherapy, fractiona-tion and treatment fields.
Recently, weekly, low-dose 'sensitising' chemotherapy plus radiation therapy has become popular, primarily due to lower toxicities when administered with radiotherapy than 'standard' dose chemotherapy.24 However, this schedule has never been looked at in a formal phase III setting, so its relative efficacy compared to standard dose chemotherapy has not been rigorously assessed.
Several meta-analyses have demonstrated that chemotherapy improves survival in patients with metastatic NSCLC (approximately 10% 1-year survival untreated vs. 35-40% 1-year survival with treatment),25'26 particularly if the chemotherapy is platin-based.14 In the past 10 years, numerous different cytotoxic drugs have become available for the treatment of lung cancer patients. These include, among others, vinorelbine, the taxanes (docetaxel and paclitaxel), gemcitabine and the topoisomerase I inhibitors (irinotecan and topotecan). Randomised studies have shown that these agents improve survival when combined with cisplatin, as compared to cisplatin alone,27'28 or the other agent alone.29'30 However, there is probably little difference in outcome between agents when combined with cisplatin, although there are clear differences in toxicity and cost.31'32
Docetaxel was recently approved for the second-line treatment of NSCLC, based upon two clinical trials. One trial compared two doses of docetaxel with best supportive care, and found an improvement in median and long-term survival, despite a low response rate of 7%.33 The other trial compared docetaxel to either vinorelbine or ifosfamide (the treatment physician was allowed to choose) and found an improvement in long-term, although not median survival.34
Given the overall poor results with standard cyto-toxic therapies and the number of advances that have been made recently in our understanding of the biology of cancer, a strong interest has emerged in targeting pathways unique to neo-plastic cells. One such example is the epidermal growth factor receptor (EGFr), which has been found to be expressed in the majority of patients with lung cancer. Based upon two phase II trials in previously treated NSCLC patients, in which response rates of 10-20% were found,35'36 two phase III trials were initiated comparing chemotherapy plus an EGFr inhibitor, ZD1839, with chemotherapy in untreated NSCLC. Somewhat surprisingly, no benefit was observed in these trials.37'38 These unexpected findings have resulted in clinical researchers, statisticians and the pharmaceutical industry re-aiming the principles of study design.
TREATMENT: SMALL-CELL LUNG CANCER
Small-cell lung cancer differs from NSCLC in a number of important ways. (1) it has a more rapid clinical course and natural history, with the rapid development of metastases, symptoms and death; (2) it exhibits features of neuroendocrine differentiation in many patients which may be distinguishable histopathologically and is associated with paraneoplastic syndromes; and (3) unlike NSCLC, SCLC is exquisitely sensitive to both chemotherapy and radiotherapy, although resistant disease often develops. Because of the rapid development of distant disease and its extreme sensitivity to the cytotoxic effects of chemotherapy, this mode of therapy forms the backbone of treatment for this disease.
A number of combination chemotherapeutic regimens are available for SCLC. With these chemotherapy regimens, overall response rates of 75-90% and complete response rates of 50% for localised disease can be anticipated. For extensive-stage disease, overall response rates of about 75% with complete response rates of 25% are common. Despite these high response rates, however, the median survival time remains about 14 months for limited-stage disease and 7 -9 months for extensive-stage disease. Less than 5% of extensive-stage patients have long-term survival of greater than 2 years.
A phase III randomised trial has been reported in abstract form, in which patients with SCLC were randomised to the control arm of etoposide and cisplatin, versus cisplatin and the topoiso-merase I inhibitor, irinotecan.39 Median survival and 1-year survival was 420 days and 60% in the cisplatin/irinotecan arm and 300 days and 40% in the cisplatin/etoposide arm. If ongoing phase III studies confirm these results, cis-platin/irinotecan would become the first combination of chemotherapy to improve survival over cisplatin/etoposide in SCLC patients in decades.
No curative regimens for patients with recurrent disease have been identified. Topotecan has a 20-40% response rate in patients with 'sensitive' SCLC, those patients who relapsed two or more months after their first-line therapy, with a median survival of 22-27 weeks. For patients with 'refractory' disease which progressed through or within 3 months of completion of first-line therapy, the response rate in phase II studies is only between 3% and 11%. Median survival is about 20 weeks.40 Results of a randomised trial comparing topotecan with CAV (cyclophosphamide, adriamycin and vincristine) as second-line therapy revealed no difference in response rates, duration of response, or survival between the two groups.41
Numerous studies have been done with chemotherapy and thoracic radiotherapy for patients with limited-stage SCLC. Conflicting results have been attributed to differences in chemotherapy regimens and different schedules integrating chemotherapy and thoracic radiation, concurrent, sequential and 'sandwich' approaches. Two recent meta-analyses concluded that thoracic radiation does result in a small but significant improvement in survival and major control of the disease in the chest, although no conclusions could be made regarding the optimal sequencing of chemotherapy and thoracic radiation.25 42
Fractionation of Radiotherapy. For limited-stage SCLC, thoracic radiotherapy has been known to improve survival, but the best ways of integrating chemotherapy and thoracic radiotherapy are uncertain. In order to settle this question, a phase III randomised clinical trial was conducted in which 417 patients with limited SCLC were randomised to receive a total of 45 Gy of radiotherapy, either twice-daily over a 3-week period or once-daily over a 5-week period, concurrently with four 21-day cycles of cisplatin plus etoposide.43 Twice-daily radiotherapy improved median survival as compared with once-daily radiotherapy (23 months vs. 19 months, p = 0.04). However, grade 3 or 4 oesophagitis was significantly more frequent with twice-daily than with once-daily fractionation (32% vs. 16%, p < 0.001).
Numerous trials have demonstrated that prophylactic brain irradiation (PCI) does not enhance survival, but does decrease the risk of brain metastases without a decrease in mental function.44 However, a recent meta-analysis demonstrated a small but statistically and clinically significant improvement in survival with PCI.45
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