Stage iv liver cancer

Stage IV non-small cell lung cancer (NSCLC) denotes the presence of metastatic disease and is largely incurable using present-day therapies. Chemotherapy remains a therapeutic option in this patient population, and there are many pertinent issues surrounding its use in patients with stage IV NSCLC. Eleven questions were framed by the American College of Chest Physicians Lung Cancer Guidelines Committee, and these were addressed by a systematic search of the available literature. The issues addressed included the identification of prognostic factors in selecting patients for chemotherapy and a critical analysis of the survival benefit provided by chemotherapy. Given the development of several new chemotherapy agents over the past decade, the impact that these agents have made was addressed as well as the definition of a standard of care regarding chemotherapeutic regimens. Given the fact that chemotherapy does not represent a curative option, other issues addressed were the optimal duration of treatment as well as its impact on symptom relief and quality of life, the role of second-line therapy, and the outcomes expectations from both first-line and second-line chemotherapy. The question of what specialty delivered the chemotherapy also was addressed. Once the data were identified, a critical analysis was undertaken attempting to objectively portray the data in support of answers for each of the questions posed. We believe the data support the fact that properly selected patients benefit from chemotherapy with regard to survival and palliation in both first-line and second-line settings. It appears that in trials addressing the duration of first-line therapy, this survival and palliative benefit occurs early, and prolonged therapy is not indicated. Therapy in this setting is cost-effective, and there are several regimens that can be considered to be "standard-of-care" options. Physicians involved in the diagnosis of these patients should be aware of the potential benefits of chemotherapy, allowing them to give recommendations to patients that are based on data derived from clinical trials. In addition, this awareness will allow them to make referrals, when appropriate, to physicians who are trained in the administration of chemotherapy and the management of patients undergoing such therapy.

Key words: chemotherapy; evidence-based medicine; guidelines; non-small cell lung cancer

Abbreviations: BSC = best supportive care; CI = confidence interval; ECOG = Eastern Cooperative Oncology Group; ELVIS = Elderly Lung Cancer Vinorelbine Italian Study; EORTC = European Organization for Research and Treatment of Cancer; FACT-L = functional assessment of cancer therapy-lung cancer; HR = hazard ratio; NSCLC = non-small cell lung cancer; OR = odds ratio; PS = performance status; QOL = quality of life; RR = relative risk; TOI = trial outcome index; TRT = thoracic radiation therapy; V/I = vinorelbine or ifosfamide

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Lung cancer remains the leading cause of cancer-related death in the United States. (1) Approximately 169,400 new cases will be diagnosed in the year 2002 with an estimated 154,900 deaths expected from this disease. (1) The vast majority of these patients have non-small cell lung cancer (NSCLC), which comprises approximately 80% of all new cases. (2) In early-stage NSCLC, surgical resection remains the standard of care in fit patients. Ongoing trials in this setting are addressing the role of both adjuvant and neoadjuvant chemotherapy. In fit patients with unresectable, locally advanced, stage III NSCLC, chemotherapy in combination with thoracic radiation therapy (TRT) is the standard of care. Controversy exists regarding the optimal strategy in combining these two modalities (ie, sequential therapy, concurrent therapy, or both) as well as regarding the optimal chemotherapeutic agents and optimal dose and schedule of TRT. In these two groups of patients, cure remains the goal in fit patients, and local modalities (ie, surgery and TRT) remain a cornerstone of therapy.

Stage IV NSCLC denotes the presence of metastatic disease. The more common sites of metastatic disease include the liver, bones, adrenal, brain, and contralateral lung. In the 1997 revision of the staging system, (3) a separate tumor nodule in the ipsilateral nonprimary tumor lobes also was classified as metastatic disease, although the possibility of multiple primary lung cancers should be considered in selected cases. In addition, there are subsets of patients with stage IIIB disease who are not appropriate for combined therapeutic modality approaches, such as those patients with a malignant pleural/ pericardial effusion and certain patients with advanced, palpable supraclavicular adenopathy. These patients are typically included with stage IV patients when the benefit of systemic chemotherapy is considered and have been included in most clinical trials addressing this issue, as the prognosis of these patients is similar to that of patients with stage IV NSCLC. Where possible, we have clearly indicated the percentage of stage IV patients in each of the trials included in this analysis.

The purpose of this section is to review the evidence supporting the role of systemic chemotherapy in the management of stage IV NSCLC. As noted above, most trials have included selected patients with stage IIIB NSCLC in whom a systemic therapeutic approach is appropriate. The 5-year survival rate of this group of patients is 1%, and therefore these patients are generally considered to be incurable. Despite this, the important issues to address include which patients are appropriate for chemotherapy, the survival and palliative impact of chemotherapy, the optimal chemotherapeutic approach, and its toxicity and outcomes expectations. To accomplish this, we sought to identify the evidence addressing these issues from primary data sources that have been published in the existing English literature. Eleven questions regarding the role of chemotherapy in treating patients with stage IV NSCLC were framed by the American College of Chest Physicians Lung Cancer Guidelines Committee. A list of MEDLINE search terms that were used to identify the primary evidence addressing these 11 questions is shown in the Appendix. In addition, the primary evidence was supplemented by the authors if data sources were identified outside the MEDLINE search mechanism. Once appropriate data sources were identified, a comprehensive review was undertaken. The evidence addressing each question is presented in detail followed by a summary state ment. All attempts to eliminate bias were made by objective presentation of the evidence as it exists in the primary data source.

ARE THERE IDENTIFIABLE PROGNOSTIC FACTORS THAT SHOULD BE USED WHEN SELECTING PATIENTS FOR SYSTEMIC CHEMOTHERAPY?

The prognosis of patients with advanced NSCLC is poor. Most large phase III trials have shown a median survival time of 8 to 10 months and a 1-year survival rate of 30 to 35%. (2) Given the consistent improvement in the survival of patients who have been treated with chemotherapy over those receiving supportive care alone, clinicians struggle to stratify these patients into different prognostic groups. One would like to identify those patients who are the most likely to benefit from aggressive chemotherapy and to tolerate its side effects, and to identify another group of patients who are unlikely to obtain any meaningful advantage from such therapy. Ideally, prognostic groups could help to stratify patients in order to apply different approaches or levels of aggression. This also could allow an appropriate focus on quality of life (QOL) as a major end point.

Individual patient characteristics seem to influence survival in patients with advanced NSCLC. The most important factor across all studies is performance status (PS). Patients with stage IV NSCLC who are compromised by their disease have poorer survival compared to patients who are less compromised. Two commonly used PS scales are shown in Table 1. At least 10 trials evaluating prognostic factors in patients with advanced NSCLC have clearly identified PS at the time of diagnosis to be a powerful predictor of survival. (4-13) In a landmark analysis of 893 patients with stage IV NSCLC, Finkelstein et al (7) documented the impact that PS had on survival. In that study, the 1-year survival rate was 36% for PS level 0 patients, 16% for PS level 1 patients, and 9% for PS level 2 patients (p < 0.001).

Pretreatment weight loss is generally regarded as a negative prognostic factor, (4,5,7,9) but not all trials have reliably corroborated this. (6,8,10,13) The sex of NSCLC patients also has been described as an important prognostic variable, with most trials suggesting improved survival for women. (6-8,12,13) Differences in survival based on patient sex have generally been small, usually [less than or equal to] 1 to 2 months.