Download Management Issues for Stage IV Non-Small

 Management Issues for Stage IV Non-Small-Cell Lung Cancer
Craig C. Earle, MD, FRCPC, and William K. Evans, MD, FRCPC
Systemic chemotherapy offers modest improvement in survival and quality of life for patients with metastatic NSCLC, and does so at a reasonable cost,
but it can be associated with toxicity.
Background:The management of stage IV non-small-cell lung cancer (NSCLC) has been a controversial subject over the past several decades. Data from
randomized trials and from phase II trials on new cancer agents are changing physician attitudes and treatment practices.
Methods: The literature on the management of metastatic lung cancer was reviewed and interpreted.
Results: There is good evidence from randomized controlled trials and meta-analyses that chemotherapy provides a modest survival benefit in stage IV
NSCLC. There is indirect evidence of improvement in quality of life, as systemic chemotherapy palliates cancer-related symptoms in the majority of
patients. New drug combinations are likely to improve recent treatment results with less morbidity than older chemotherapy regimens. Despite the relatively
high cost of these treatments, chemotherapy is cost effective in the Canadian health care environment relative to other accepted medical interventions.
Conclusions: Chemotherapy will play an increasing role in the management of patients with advanced NSCLC.
Introduction
Lung cancer is the leading cause of cancer death in North America, and non-small-cell lung cancer (NSCLC) -- squamous, adenocarcinoma, and large-cell carcinoma
-- is the dominant histology, being responsible for 75% to 80% of all lung malignancies. Approximately 40% to 50% of those patients present with incurable metastatic
(stage IV) disease.1 Because of early hematogenous spread, most of those presenting with earlier-stage disease will eventually develop metastases and become
candidates for systemic therapy.
The addition of chemotherapy to the supportive, symptomatic care of patients with metastatic NSCLC remains controversial. Despite decades of clinical investigation,
the treatment of stage IV NSCLC remains unsatisfactory. There is no treatment with curative potential, and even the most active regimens have complete response
rates of less than 5%.1 While systemic chemotherapy offers the possibility of temporary disease control, an improvement in quality of life, and a modest increase in
survival, many clinicians have concerns that these limited benefits do not justify the toxicity and expense associated with treatment. Most of the currently used
chemotherapy regimens are based on cisplatin, usually in combination with a plant alkaloid such as etoposide or a vinca. However, several new agents with promising
activity against NSCLC have recently been added to the therapeutic armamentarium against NSCLC that yield higher response rates, improved one-year survival rates,
and lower toxicity.
Improving Survival in Stage IV NSCLC
The only therapeutic modality that can consistently cure a subset of patients with NSCLC is surgery. In metastatic disease, the role of surgery is restricted to the
management of solitary metastases. Resection of either noncontiguous synchronous or metachronous lung metastases, as well as synchronous solitary adrenal lesions,
has been reported to cure a minority of patients.2 The brain will be the only site of recurrence in approximately 6% of patients with completely resected NSCLC.3
Nearly half of these metastases will be solitary. Compared with radiation alone, surgical excision of brain metastases followed by radiation prolongs median survival
from 3.4 months to 9.2 months and provides a better quality of life.4 There have been no reports of long-term survival after removal of liver, bone, or skin metastases,
as these usually are not solitary metastatic foci.5
Several studies have attempted to define those prognostic features that are important for survival in advanced NSCLC. Good performance status, female gender, and
absence of extrathoracic disease consistently have been associated with a more favorable outcome.6 Some studies have shown that poor prognostic features are weight
loss, particular metastatic sites such as the brain, or the overall number of metastatic sites.7 Histologic subtype, on the other hand, does not appear to significantly affect
prognosis.
As previously noted, approximately half of all NSCLC patients present with metastatic disease. Furthermore, when patients relapse following complete surgical
resection, it is as distant metastases in 75% of cases. Effective systemic therapies are necessary to improve current surgical results in NSCLC. Active agents in
NSCLC achieve major tumor regression in only 15% to 25% of patients (Table 1). They virtually never induce complete remissions (CRs), and single agents have little
or no impact on overall survival.1 Therefore, it is not surprising that empiric combinations of these drugs produce only modest antitumor activity and that no specific
combination has emerged as the clear standard of practice. The current best combinations cause partial regressions in 30% to 40% of patients with stage IV disease
(Table 2), a rare CR, a fairly consistent median survival time of six to nine months, and survival at one year of approximately 20% to 30%.6 Given this degree of
activity, some clinicians have argued against using cytotoxic agents in metastatic NSCLC. Recent data, however, suggest that a position of therapeutic nihilism is
inappropriate.
Published randomized trials of polychemotherapy vs supportive care in advanced NSCLC have produced a literature of conflicting small trials.8 Several attempts have
been made to summarize this evidence by meta-analysis. Four such meta-analyses addressed the question of whether chemotherapy increases survival in advanced
NSCLC, and all showed a benefit with chemotherapy.8-11
The largest, by the Non-Small-Cell Lung Cancer Collaborative Group (NSCLCCG),9 incorporated individual updated data in 11 trials of 1,190 patients with stage
IIIB or IV disease. The NSCLCCG found a pooled hazard ratio of death of 0.73 (95% CI [confidence interval] = 0.63 to 0.85) at one year for patients treated with
cisplatin-containing chemotherapy regimens compared with those managed with supportive care only (Fig 1). The absolute survival benefit at one year was 10% (95%
CI = 5% to 15%), increasing from 16% to 26% (PLEASE SEE HARD COPY OF JOURNAL FOR FIGURE 2.) The gain in median survival was 1.5 months (95%
CI = 1 to 2.5 months). No additional survival advantage was seen after six months. The use of long-term alkylating agents actually had a negative effect on survival.
Although authors have interpreted the clinical significance of this difference to argue both for12 and against13 the use of chemotherapy in NSCLC, it is nonetheless proof
that chemotherapy produces a biologic effect. Furthermore, as noted by Le Chevalier,14 an increase in median survival of one to two months may represent as much as
a six-month increase in survival for the 20% to 30% of patients who have the best response. If these patients could be identified, treatment could be targeted more
effectively.
Subgroup analysis of the NSCLCCG meta-analysis was unable to identify groups of patients less likely to benefit from treatment based on age, sex, histology,
performance status, or stage of disease (metastatic vs nonmetastatic). When the survival results were divided into six-month periods, a significant risk reduction was
seen in only the first six-month period. All trials excluded patients with poor performance status (Eastern Cooperative Oncology Group status = >2; Karnofsky index =
<50) as they have historically had extremely short survival and virtually never respond to chemotherapy.
The other three meta-analyses showed similar results. These studies did not use individual patient data, however, and were therefore unable to separate stage IIIB
patients from stage IV patients. Marino and colleagues10 included eight randomized trials and found that median survival increased from 3.9 to 6.7 months for the
chemotherapy-treated group over best supportive care alone. Their endpoint was the odds ratio of death at six months, which was 0.44 (95% CI = 0.32 to 0.59).
Souquet et al8 analyzed seven studies to derive a relative risk of death of 0.91 at one year. Grilli et al11 demonstrated a relative risk of one-year mortality of 0.76 (95%
CI = 0.66 to 0.87) and a six-week average prolongation of survival with analysis restricted to six trials.
Although meta-analyses can achieve significant power, they must be viewed with caution. They are prone to publication bias toward positive results as well as to any
other biases contained in the originally published data. There have been several recent unsettling examples of meta-analyses that were later refuted by large randomized
trials.15 In the analyses described above, the variable inclusion of stage IIIB patients in some trials has resulted in an inhomogeneity of the study population that may
confound the results, as stage IIIB patients often have better responses to systemic therapy.1 Furthermore, for several trials, the one-year survival had to be extracted
from published survival curves, which may have decreased the accuracy of the data. Lastly, several different chemotherapy regimens were grouped together for
comparison with supportive care, making it difficult to draw conclusions about the effectiveness of any one regimen. Large, definitive randomized trials are needed but
are difficult to organize.16
Palliation of Metastatic NSCLC
Most patients with metastatic NSCLC have disease-related symptoms at the time of diagnosis.17 Table 3 shows the frequency of common symptoms of lung cancer in
patients with advanced NSCLC. Fatigue and decreased activity are the most common complaints, followed by cough and dyspnea. Symptoms in an individual patient
are dependent on the particular site(s) of metastases.
Surgical palliation of symptoms includes drainage and pleurodesis of malignant pleural and pericardial effusions, as well as occasional endobronchial stenting of an
obstructing lesion or removal of a tumor that causes persistent, serious hemoptysis.18 Resection in this situation is usually kept to the minimum needed for relief.
Bronchoscopic techniques such as laser resection are employed where possible. Surgical fixation of bone followed by irradiation is necessary to manage pathologic
fractures.
Radiation can be effective in palliating bone pain, hemoptysis, or symptomatic brain metastases. Furthermore, it can be used if complications occur (eg, spinal cord
compression, superior vena caval obstruction, or obstructive lobar collapse).19 There is randomized evidence that radiation therapy can effectively palliate symptoms
and improve performance status.5 Also, intraluminal brachytherapy, with or without endoluminal laser treatment, has shown benefit in selected cases with hemoptysis or
dyspnea related to the primary tumor.20
Those who oppose systemic treatment for patients with metastatic NSCLC claim that the survival benefits are too small to justify its use. While this may be true for
many patients, it is paternalistic for physicians to make this decision unilaterally for patients. There is ample evidence that a survival benefit of several months may be
valued much more by a patient with only a few months to live than by health professionals or by healthy members of the general population.21,22 A 1995 survey of
Canadian oncologists reported that 79% of physicians would suggest no specific treatment for stage IV NSCLC. The respondents generally underestimated the value
of chemotherapy while overestimating the benefits of radiotherapy.23 These results were essentially unchanged from a previous survey in 1986.22
The effect of chemotherapy on quality of life has rarely been formally addressed; however, there is indirect evidence of benefit. Chemotherapy reduces symptoms such
as pain, cough, hemoptysis, and dyspnea in approximately 70% of patients (Table 4),24-28 and improvements in performance status and weight gain have been
reported.27,28 Such symptomatic improvement can occur in the absence of objective response.25
The average duration of symptom control is short, with benefit lasting an average of six to eight weeks.28 Nevertheless, a large Canadian trial showed that
chemotherapy-treated patients were hospitalized fewer days than those who received supportive care alone (17.1 vs 23.6 days, respectively) and required less
palliative radiotherapy. These observations suggest that chemotherapy results in fewer clinical symptoms and possible improved quality of life.29
Studies are needed that formally assess the quality of life of lung cancer patients who are undergoing chemotherapy. Attempts to capture this in clinical trials have been
hindered by the rapid deterioration of many patients who are either unable or unwilling to complete the questionnaires on quality of life after one or two treatment
cycles.30,31 This has led some to contend that chemotherapy causes deterioration in quality of life. However, a clinical trial from Norway32 that succeeded in comparing
the quality of life of lung cancer patients randomized between chemotherapy and radiotherapy found no difference between the two groups. Other uncontrolled studies
have also found relatively preserved quality of life in NSCLC patients who were being treated with chemotherapy.33-35
Another difficulty in measuring quality of life is its inherent subjectivity. Physicians may be overly optimistic about the positive effects of medical treatment on quality of
life.33 Several instruments to measure quality of life have been developed specifically for lung cancer, such as the Functional Assessment of Cancer Therapy (FACT-L),
the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire (EORTC-QLQ-LC13), and the Lung Cancer Symptom Scale
(LCSS).36 This proliferation of quality-of-life instruments has made it difficult to compare the results from studies that use different scales.
Chemotherapy can palliate symptoms for patients with NSCLC but at the expense of nontrivial toxicity. Approximately 35% to 50% of patients in randomized
chemotherapy trials experience some form of severe side effect, and the overall risk of lethal toxicity is 1%.6 Advances in supportive care, such as the use of serotonin
antagonist antiemetics and hematopoietic growth factors, have markedly reduced the side effects of treatment and have improved the therapeutic index. Furthermore,
current chemotherapy regimens are less toxic than previous ones. For example, the lack of hair loss associated with the vinorelbine-cisplatin combination has made this
therapy more acceptable among patients. As a result, the quality of life of many patients probably improves despite treatment-related toxicity. However, this impression
requires objective confirmation.
Lastly, the psychologic benefit from undergoing an active treatment as opposed to being told to "get your affairs in order" or "take a vacation" should not be discounted.
Recurrent suggestions in the literature indicate that patients with a "fighting spirit" seem to fare better than those who do not have this characteristic.12 Physician attitude
and a concrete treatment plan may contribute to this positive mental state.
Economics of Treating Advanced Disease
Lung cancer is a relatively inexpensive disease to manage. Because of its prevalence, however, it constitutes a significant proportion of total health care expenditures.37
The University of Ottawa and Statistics Canada have collaborated to determine the direct costs of lung cancer diagnosis and treatment by disease stage and cell type in
Canada.38 The cost of managing a patient with stage IV lung cancer with supportive care alone from diagnosis to death was approximately $28,000 in 1995 Canadian
dollars. Since approximately 5,000 patients will present with metastatic NSCLC each year in Canada (and about 10 times as many in the United States), the total cost
to the Canadian health care system of managing stage IV disease is approximately $150 million. Not surprisingly, the majority of this cost, $132 million, is spent in the
first year of illness after diagnosis. Hospitalization during the initial diagnostic workup constitutes approximately one third of the total cost. Terminal care accounts for
about half of the total cost whether a patient receives chemotherapy or not. As a result, continuing present trends toward ambulatory diagnostic assessment and
treatment, as well as optimizing community-based terminal care, will have the greatest impact on reducing costs.39
In a time of increasing fiscal restraint in health care budgets, the appropriateness of offering relatively expensive cytotoxic agents with limited impact on survival and
quality of life presents an understandable concern. However, a cost analysis performed by the National Cancer Institute of Canada (NCIC) on a multicenter
randomized trial comparing chemotherapy with best supportive care showed that chemotherapy can be cost effective -- and can even lead to a net savings -- by
reducing both the palliative measures and the length of terminal care hospitalization.29 When the cost of introducing some of the newer, more expensive
chemotherapeutic agents is considered, treatment can still be cost effective.
We compared the costs of several new drugs with the survival advantage they appear to provide from phase II studies. For example, for life-year gained, gemcitabine
costs between $3,000 and $6,000 Canadian dollars,40 paclitaxel costs $4,778,39 and vinorelbine with cisplatin costs $5,551.41 Assuming quality of life is reasonable
while on treatment, this falls well within accepted guidelines for cost effectiveness42 and compares favorably with many accepted but expensive medical therapies.29
Despite being cost effective, chemotherapy treatment for all stage IV NSCLC patients would create a significant burden on both finances and manpower by virtue of its
frequency. As advances in cancer research provide more cost-effective treatments, we are forced to question how many cost-effective treatments we can afford.
Oncologists in Canada are still relatively more conservative in their management of advanced NSCLC than their American colleagues.23 Also, many patients are not
candidates for systemic therapy due to biologic age, performance status, or comorbid conditions. As a result, the actual impact of a new treatment on health budgets is
likely to be less than might otherwise be projected.
In Canada, universal health coverage is threatened by its rapidly increasing societal cost. To guide the expenditure of public moneys, evidence-based medicine and
practice guidelines are being developed. The Ontario Cancer Treatment Practice Guidelines Initiative, a multidisciplinary group developing evidence-based guidelines
sponsored in part by the Ontario Ministry of Health, has recommended that it is "reasonable to offer cisplatin-based chemotherapy to medically suitable patients as a
treatment option"; for survival, symptom control, and outcomes of quality of life in metastatic NSCLC patients.43 In the United States, managed care is playing an
increasingly powerful role in treatment decisions. While health maintenance organizations (HMOs) have been successful in controlling costs, there is concern that some
of this success comes from a philosophy of denying patients access to expensive treatments that might not be beneficial. Primary care physicians acting as gatekeepers
are forced into a conflict of trying to serve both the interests of their patients and those of their employers when deciding whether a patient should even see an
oncologist. Thus, establishing the cost effectiveness of a new treatment is important in both countries.
Treatment Issues
Patients must be carefully selected for chemotherapy. Response to treatment and prognosis are most closely related to performance status. Patients with even
moderately impaired ambulation, for example, have reduced survival and greatly increased toxicity when compared with more mobile patients.44 Therefore, therapy
should be offered only to patients in relatively good physical condition.
Next, a chemotherapy regimen must be selected. There is little evidence that establishes the superiority of one commonly used combination over another. Cisplatin has
emerged as the most important component of current NSCLC chemotherapy regimens. Optimal platinum dosages or combinations, however, cannot be determined
from the present literature. There is evidence that protocols delivering cisplatin at doses of 100 mg/m2 produce higher response rates than less intensive regimens,
although survival is not prolonged.45
Cisplatin with vinorelbine has become a popular combination over the past several years because of its favorable toxicity profile. Specifically, the lesser degree of hair
loss with these drugs has been an important factor in patient acceptance. Table 2 shows a commonly used schedule. Randomized studies have demonstrated that
vinorelbine with cisplatin can produce superior response and survival outcomes when compared with cisplatin alone,46 vindesine plus cisplatin, and vinorelbine alone.47
A three-arm phase III study by the Eastern Cooperative Oncology Group was published in abstract form in the 1996 Proceedings of the American Society of
Clinical Oncology. This study compared cisplatin plus etoposide vs cisplatin plus paclitaxel at two different dose levels, either with or without granulocyte colonystimulating factor (G-CSF).48 The response rates were higher in the paclitaxel-containing regimens: 27% without G-CSF and 32% with G-CSF vs 12% for the
etoposide/cisplatin regimen. There was a trend towards improved one-year survival: 39% of patients treated with paclitaxel plus cisplatin with G-CSF were alive at one
year vs 32% of those receiving etoposide plus cisplatin. Another randomized trial is underway comparing 200 mg/m2 of paclitaxel with supportive care alone in patients
with inoperable NSCLC.
A similar regimen using carboplatin is also being used. Since carboplatin does not significantly add to paclitaxel's neurotoxicity, a combination of these two drugs has
been successful. Response rates of 27% to 62% have been reported, including some complete responses. The median survival of patients in these trials ranged from
8.7 to 12.5 months, and the one-year survival ranged from 37% to 54%.49-51
Most protocols give paclitaxel as a continuous infusion over three or 24 hours. Because longer infusions consume more resources, we recently performed a phase II
study of paclitaxel and carboplatin with paclitaxel given as a one-hour infusion at an average dose of 188 mg/m2. Although it was extremely well tolerated and yielded
some impressive responses (Fig 3), we observed a response rate of only 29%, suggesting that shorter infusions may not be as efficacious as longer infusions.
The optimal duration of treatment with any of these regimens is not clear. The usual practice is to treat for two to three cycles to determine tolerance and to evaluate
response. If there is evidence of response, treatment is continued for six to eight cycles. If there is no evidence of a response, treatment is commonly stopped or the
regimen is changed. However, abandoning treatment due to lack of response after a few cycles may deprive some patients of a useful treatment. There is randomized
evidence that NSCLC patients with stable disease on chemotherapy have similar survival to those with objective responses.52 Furthermore, Finkelstein et al53 found
that patients who responded very slowly fared as well or better than those who responded quickly. Similar phenomena have been observed in multiple myeloma54 and
lymphoma.55 The taxanes in particular have been noted to cause late responses in patients with lung cancer or breast cancer.56 As a result, minimally responding
patients may benefit from persisting with treatment unless toxicity outweighs any potential benefit.
These observations suggest that a treatment resulting in stability in a disease that is usually rapidly progressive may have significant antitumor activity. Furthermore,
experience with neoadjuvant chemotherapy in earlier-stage disease has taught us that at the time of surgery, an unshrinking tumor mass may consist of mostly fibrosis or
necrotic debris that would not be evident with noninvasive imaging.57
Whether to continue treatment beyond six months in responding patients is the next question to be answered. In the meta-analyses described previously, the survival
advantage in the treatment arm was lost after six months. With a median survival of approximately six months in the treated group, this is not a surprising finding. In
addition, many of the trials used chemotherapy protocols that did not allow treatment to continue beyond six cycles.9 Whether patients who are doing well on
chemotherapy after six cycles benefit from continuing until there is a reason to stop has not been tested. Presently, clinicians must use their own judgment and the values
of their patients to decide in each specific situation.
While few oncologists offer a second-line regimen if a patient fails first-line treatment, we now have an agent, docetaxel, that has shown an encouraging 17% response
rate in patients who were resistant to platinum-based chemotherapy.58 However, patients who have been refractory to first-line agents generally are unlikely to benefit
from second-line treatment.
New Chemotherapeutic Agents
Optimism about improving the results of treatment for NSCLC is high among physicians who treat patients with this disease. An unprecedented number of new agents
are in clinical trials with single-agent response rates over 15%.59 These agents have arguably less toxicity, and many appear to have higher response rates compared
with current drugs.6
The taxanes have shown impressive activity in a number of human cancers, including NSCLC.60 Both paclitaxel and its semisynthetic analogue, docetaxel, have shown
response rates above 20% in uncontrolled trials.61-63 Paclitaxel is particularly interesting because of reported survival rates of 40% at one year.61,64 The major
toxicities of paclitaxel are myelosuppression, peripheral neuropathy, alopecia, and myalgias. Allergic reactions to the castor oil diluant are common but can be
prevented by prophylaxis with corticosteroids and histamine antagonists. Docetaxel has a similar toxicity profile, with the addition of a capillary leak syndrome that also
can be prevented with corticosteroids. As described above, it may have useful action as a second-line agent.
Irinotecan (CPT-11), a camptothecin, has shown promising results in phase II trials, both alone (where response rates over 30% have been seen)65 and in combination
with other agents.66 The dose-limiting toxicity is severe diarrhea. A related compound, topotecan, has shown less impressive activity.67 Gemcitabine, the pyrimidine
antimetabolite, also has demonstrated response rates of over 20% in phase II studies.68 Response rates of 30% to 58% have been reported when gemcitabine is
combined with agents such as cisplatin.69
All of these results must be viewed with caution, however, as there is a poor correlation between tumor response and subsequent survival, especially when generalizing
to a larger population with less favorable prognostic factors than the phase II study population.13
Eligible patients with metastatic NSCLC should be encouraged to participate in clinical trials where possible. Currently, only 1% of all patients with NSCLC in the
United States are enrolled in clinical trials.70 With careful observation of the efficacy and toxicity of new regimens, we will be able to more effectively manage this major
public health problem. Whether it is ethical to include a no-treatment arm has been a subject of considerable debate.11 The equipoise between chemotherapy and
supportive care alone varies considerably among investigators.
Future Treatment Modalities
In addition to new chemotherapeutic agents, several biologic strategies are being investigated. Gene therapy attempts either to insert an antioncogene into tumor cells to
suppress an active oncogene or to insert a wild-type gene where tumor suppressor genes have been inactivated.59 Antisense oligonucleotides and antisense RNA have
been shown to inhibit tumor growth both in vitro and in animal models.71 Unfortunately, delivery and uptake of the antisense product are difficult. Methods have
included viral vectors, liposomes, and direct injection72; however, catabolism is rapid in vivo.73
Matrix metalloproteinases are enzymes secreted by cancer cells to digest connective tissue. These enzymes are required for a metastatic cell to implant. Several agents
have been developed that inhibit these enzymes and limit invasion by malignant cells in vivo and in animal models.74 Differentiating agents, antioxidants, and angiogenesis
inhibitors are other strategies that hold promise for the future.59
Conclusions
Patients with stage IV NSCLC and good performance status may realize a modest improvement in survival with cisplatin-based chemotherapy. While the chances of
improving specific symptoms are good, the effect on overall quality of life is unclear when treatment-related toxicity is considered. The decision to use chemotherapy
must incorporate physician judgment and patient values on a case-by-case basis. Chemotherapy should at least be offered as an option to all eligible patients. The costeffectiveness of treatment for NSCLC is comparable to that of many other accepted medical therapies, and cost should not be considered a barrier. Since the degree
of benefit from current therapies is small, it is appropriate to consider previously untreated patients for trials of investigational agents. Randomized trials of new
chemotherapy regimens that also assess quality of life are needed to define the future practice standard.
References
1. Ihde DC. Chemotherapy of lung cancer. N Engl J Med. 1992;327:1434-1441.
2. Reyes L, Parvez Z, Nemoto T, et al. Adrenalectomy for adrenal metastasis from lung carcinoma. J Surg Oncol. 1990;44:32-34.
3. Figlin RA, Piantadosi S, Feld R, et al. Intracranial recurrence of carcinoma after complete surgical resection of stage I, II and III non-small cell lung cancer. N
Engl J Med. 1988;318:1300-1305.
4. Patchell RA, Tibbs PA, Walsh JW. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322:494-500.
5. DeVita VT Jr, Hellman S, Rosenberg SA, eds. Cancer: Principles and Practice of Oncology. Philadelphia, Pa: JB Lippincott Co; 1993:696.
6. Thatcher N, Ranson M, Lee SM, et al. Chemotherapy in non-small cell lung cancer. Ann Oncol. 1995;6:S83-S95.
7. Lanzotti VJ, Thomas DR, Boyle LE, et al. Survival with inoperable lung cancer: an integration of prognostic variables based on simple clinical criteria. Cancer.
1977;39:303-313.
8. Souquet PJ, Chauvin F, Boissel JP, et al. Polychemotherapy in advanced non small cell lung cancer: a meta-analysis. Lancet. 1993;342:19-21.
9. Non-Small Cell Lung Cancer Collaborative Group. Chemotherapy in non-small cell lung cancer: a meta-analysis using updated data on individual patients from
52 randomised clinical trials. Br Med J. 1995;311:899-909.
10. Marino P, Pampallona S, Preatoni A, et al. Chemotherapy vs supportive care in advanced non-small-cell lung cancer: results of a meta-analysis of the literature.
Chest. 1994;106:861-865.
11. Grilli R, Oxman AD, Julian JA. Chemotherapy for advanced non-small-cell lung cancer: how much benefit is enough? J Clin Oncol. 1993;11:1866-1872.
12. Masters GA, Vokes EE. Should non-small cell carcinoma of the lung be treated with chemotherapy? Pro: chemotherapy is for non-small cell lung cancer. Am J
Respir Crit Care Med. 1995;151:1285-1287.
13. Douglas IS, White SR. Con: therapeutic empiricism - the case against chemotherapy in non-small cell lung cancer. Am J Respir Crit Care Med.
1995;151:1288-1291.
14. Le Chevalier T. Chemotherapy for advanced NSCLC: will meta-analysis provide the answer? Chest. 1996;109:107S-109S.
15. Cappelleri JC, Ioannidis JPA, Schmid CH, et al. Large trials vs meta-analysis of smaller trials: how do their results compare?. JAMA. 1996;276:1332-1338.
16. McVie JG. Chemotherapy for advanced disease: how to raise enthusiasm. Chest. 1996;109:80S-82S.
17. Hopwood P, Stephens RJ. Symptoms at presentation for treatment in patients with lung cancer: implications for the evaluation of palliative treatment. Br J
Cancer. 1995;71:633-636.
18. Abratt RP. IASLC Workshop on Improving Quality of Life and the Supportive Management of Patients with Lung Cancer. Lung Cancer. 1994;10:375-380.
19. Jackson M, Ball D. Palliative retreatment of locally recurrent lung cancer after radical radiotherapy. Med J Aust. 1987;147:391-394.
20. Seagren S, Harrell J. Prospective trial of palliative high dose rate endobronchial irradiation with or without laser for recurrent non-small cell lung cancer. Proc
Annu Meet Am Soc Clin Oncol. 1990;9:A863.
21. Slevin ML, Stubbs L, Plant HJ, et al. Attitudes to chemotherapy: comparing views of patients with cancer with those of doctors, nurses, and general public. Br
Med J. 1990;300:1458-1460.
22. Mackillop WJ, OíSullivan B, Ward GK. Non-small cell lung cancer: how oncologists want to be treated. Int J Radiat Oncol Biol Phys. 1987;13:929-934.
23. Raby B, Pater J, Mackillop W. Does knowledge guide practice? Another look at the management of non-small-cell lung cancer. J Clin Oncol. 1995;13:19041911.
24. Ellis PA, Smith IE, Hardy JR, et al. Symptom relief with MVP (mitomycin C, vinblastine and cisplatin) chemotherapy in advanced non-small cell lung cancer. Br
J Cancer. 1995;71:366-370.
25. Fernandez C, Rosell R, Abad-Esteve A. Quality of life during chemotherapy in non-small cell lung cancer patients. Acta Oncol. 1989;28:129-133.
26. Osoba D, Rusthoven JJ, Turnbull KA, et al. Combination chemotherapy with bleomycin, etoposide and cisplatin in metastatic non-small cell lung cancer. J Clin
Oncol. 1985;3:1478-1485.
27. Kris MG, Gralla RJ, Potanovich LM, et al. Assessment of pretreatment symptoms and improvement after EDAM + mitomycin + vinblastine (EMV) in patients
with inoperable non-small cell lung cancer. Proc Annu Meet Am Soc Clin Oncol. 1990;9:A883.
28. Hardy JR, Noble T, Smith IE. Symptom relief with moderate dose chemotherapy (mitomycin-C, vinblastine, and cisplatin) in advanced non-small cell lung
cancer. Br J Cancer. 1989;60:764-766.
29. Jaakkimainen L, Goodwin PJ, Pater J. Counting the costs of chemotherapy in a National Cancer Institute of Canada randomized trial in non-small cell lung
cancer. J Clin Oncol. 1990;8:1301-1309.
30. Ganz PA, Figlin RA, Haskell CM, et al. Supportive care versus supportive care and combination chemotherapy in metastatic non-small cell lung cancer.
Cancer. 1989;63:1271-1278.
31. Rapp E, Pater JL, Willan A, et al. Chemotherapy can prolong survival in patients with advanced non-small-cell lung cancer: report of a Canadian multicenter
randomized trial. J Clin Oncol. 1988;6:633-641.
32. Kaasa S, Mastekaasa A, Naess S. Quality of life of lung cancer patients in a randomized clinical trial evaluated by a psychological well-being questionnaire.
Acta Oncol. 1988;27:335-342.
33. Kosmidis P. Quality of life as a new end point. Chest. 1996;109:110S-112S.
34. Hollen PJ, Gralla RJ, Kris MG, et al. Quality of life during clinical trials: conceptual model for the Lung Cancer Symptom Scale (LCSS). Support Care Cancer.
1994;2:213-222.
35. Osoba D, Murray M, Gelmon K, et al. Quality of life, appetite, and weight change in patients receiving dose-intensive chemotherapy. Oncology. 1994;8:61-69.
36. Hollen PJ, Gralla RJ, Kris MG, et al. Quality of life assessment in individuals with lung cancer: testing the Lung Cancer Symptom Scale (LCSS). Eur J Cancer.
1993;29A:S51-S58.
37. Evans WK, Will BP, Berthelot JM, et al. The cost of managing lung cancer in Canada. Oncology. 1995;9:147-153.
38. Evans WK, Will BP, Berthelot JM, et al. Diagnostic and therapeutic approaches to lung cancer in Canada and their costs. Br J Cancer. 1995;72:1270-1277.
39. Earle CC, Evans WK. A comparison of the cost of paclitaxel
versus best supportive care in stage IV non-small cell lung cancer. Cancer Prev Control. 1997. In press.
40. Evans WK. An estimate of the cost effectiveness of gemcitabine in stage IV non-small cell lung cancer. Semin Oncol. 1996;23:82-89.
41. Evans WK, Le Chevalier T. The cost-effectiveness of navelbine alone or in combination with cisplatin in comparison to standard therapies in stage IV non-small
cell lung cancer. Eur J Cancer. 1996;32A:2249-2255.
42. Laupacis A, Feeny D, Detsky A, et al. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using
clinical and economic evaluations. Can Med Assoc J. 1992;146:473-481.
43. Lopez PG, Stewart DJ, Newman TE, et al. Chemotherapy in stage IV (metastatic) non-small-cell lung cancer. Cancer Prev Control. 1997;1:18-27.
44. Ruckdeschel JC, Finkelstein DM, Ettinger DS, et al. A randomized trial of the four most active regimens for metastatic non-small-cell lung cancer. J Clin Oncol.
1986;4:14-22.
45. Donnadieu M, Paesmans M, Sculier J. Chemotherapy of non-small cell lung cancer according to disease extent: a meta-analysis of the literature. Lung Cancer.
1991;7:243-252.
46. Wozniak AJ, Crowley JJ, Balcerzak SP, et al. Randomized phase III trial of cisplatin (CDDP) vs CDDP plus navelbine in treatment of advanced non-small cell
lung cancer (NSCLC): report of a Southwest Oncology Group study (SWOG-9308). Proc Annu Meet Am Soc Clin Oncol. 1996;15:A1110.
47. Le Chevalier T, Brisgand D, Douillard JL, et al. Randomized study of vinorelbine and cisplatin versus vindesine and cisplatin versus vinorelbine alone in
advanced non-small cell lung cancer: results of a European multicenter trial including 612 patients. J Clin Oncol. 1994;12:360-367.
48. Bonomi P, Kim K, Chang A, et al. Phase III trial comparing etoposide (E) cisplatin (C) versus taxol (T) with cisplatin-G-CSF (G) versus taxol-cisplatin in
advanced non-small cell lung cancer. An Eastern Cooperative Oncology Group (ECOG) trial. Proc Annu Meet Am Soc Clin Oncol. 1996;15:A1145.
49. Langer CJ, Leighton JC, Comis RL, et al. Paclitaxel and carboplatin in combination in the treatment of advanced non-small-cell lung cancer: a phase II toxicity,
response, and survival analysis. J Clin Oncol. 1995;13:1860-1870.
50. Johnson DH, Paul DM, Hande KR, et al. Paclitaxel plus carboplatin for advanced lung cancer: preliminary results of a Vanderbilt University phase II trial LUN-46. Semin Oncol. 1995;22:30-33.
51. Johnson D, Paul D, Hande K, et al. Paclitaxel plus carboplatin in advanced non-small-cell lung cancer: a phase II trial. J Clin Oncol. 1996;14:2054-2060.
52. Murray N, Coppin C, Coldman A, et al. Drug delivery analysis of the Canadian multicenter trial in non-small-cell lung cancer. J Clin Oncol. 1994;12:23332339.
53. Finkelstein DM, Ettinger DS, Ruckdeschel JC. Long-term survivors in metastatic non-small-cell lung cancer: an ECOG study. J Clin Oncol. 1986;4:702-709.
54. Bergsagel DE. The role of chemotherapy in the treatment of multiple myeloma. Baillieres Clin Haematol. 1995;8:783-794.
55. Verdonck LF, van Putten WL, Hagenbeek A, et al. Comparison of CHOP chemotherapy with autologous bone marrow transplantation for slowly responding
patients with aggressive non-Hodgkin's lymphoma. N Engl J Med. 1995;332:1045-1051.
56. Gianni L. Paclitaxel in breast cancer: early and advanced stages of the disease. Curr Oncol. 1995;2:4-6.
57. Pisters KM, Kris MG, Gralla RJ, et al. Pathologic complete response in advanced non-small-cell lung cancer following preoperative chemotherapy: implications
for the design of future non-small-cell lung cancer combined modality trials. J Clin Oncol. 1993;11:1757-1762.
58. Fossella FV, Lee JS, Shin DM. Phase II study of docetaxel for advanced or metastatic platinum-refractory non-small-cell lung cancer. J Clin Oncol.
1995;13:645-651.
59. Goss GD, Dahrouge S, Lochrin CA. Recent advances in the treatment of non-small cell lung cancer. Anticancer Drugs. 1996;7:363-385.
60. Rowinsky EK, Donehower RC. Drug therapy: paclitaxel (Taxol). N Engl J Med. 1995;332:1004-1014.
61. Chang AY, Kim K, Glick J, et al. Phase II study of Taxol, merbarone, and piroxantrone in stage IV non-small-cell lung cancer: the Eastern Cooperative
Oncology Group results. J Natl Cancer Inst. 1993;85:388-393.
62. Fossella F, Lee J, Murphy W. Phase II study of docetaxel for recurrent or metastatic non-small cell lung cancer. J Clin Oncol. 1994;12:1238-1244.
63. Francis P, Rigas J, Kris M, et al. Phase II trial of docetaxel in patients with stage III and IV non-small cell lung cancer. J Clin Oncol. 1994;12:1232-1237.
64. Murphy WK, Fosella FW, Winn RJ, et al. Phase II study of Taxol in patients with untreated advanced non-small-cell lung cancer. J Natl Cancer Inst.
1993;85:384-388.
65. Fukuoka M, Niitani H, Suzuki A, et al. A phase II study of CPT-11, a new derivative of camptothecin, for previously untreated non-small cell lung cancer. J
Clin Oncol. 1992;10:16-20.
66. Masuda N, Fukuoka M, Takada M, et al. CPT-11 in combination with cisplatin for advanced non-small cell lung cancer. J Clin Oncol. 1992;10:1775-1780.
67. Weitz J, Jung S, Marschke RF, et al. Randomized phase II trial of two schedules of topotecan for the treatment of advanced stage non-small cell lung carcinoma
(NSCLC): a North Central Cancer Treatment Group (NCCTG) trial. Proc Annu Meet Am Soc Clin Oncol. 1995;14:A1053.
68. Abratt RP, Bezwoda W, Falkson G, et al. Efficacy and safety profile of gemcitabine in non-small cell lung cancer: a phase II study. J Clin Oncol.
1994;12:1535-1540.
69. Crino L, Scagliotti G, Marangolo M. Cisplatin-gemcitabine combination in non-small cell lung cancer: a phase II study. Proc Annu Meet Am Soc Clin Oncol.
1995;14:A1066.
70. Jett JR. Current treatment of unresectable lung cancer. Mayo Clin Proc. 1993;68:603-611.
71. Akhtar S, Ivinson AJ. Therapies that make sense. Nat Genet. 1993;4:215-217.
72. Ma DD, Le Doan T. Antisense oligonucleotide therapies: are they the "magic bullets"? Ann Intern Med. 1994;120:161-162.
73. Askari FK, McDonnell WM. Antisense-oligonucleotide therapy. N Engl J Med. 1996;334:316-318.
74. Tannock IF, Hill RP. The Basic Science of Oncology. Toronto, Canada: McGraw-Hill, Inc; 1992:183,348.
75. Woods RL, Williams CJ, Levi J, et al. A randomised trial of cisplatin and vindesine versus supportive care only in advanced non-small cell lung cancer. Br J
Cancer. 1990;61:608-611.
76. Kaasa S, Lund E, Thorud E, et al. Symptomatic treatment versus combination chemotherapy for patients with extensive non-small cell lung cancer. Cancer.
1991;67:2443-2447.
77. Cellerino R, Tummarello D, Guidi F, et al. A randomized trial of alternating chemotherapy versus best supportive care in advanced non-small cell lung cancer. J
Clin Oncol. 1991;9:1453-1461.
78. Cartei G, Cartei F, Cantone A, et al. Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with supportive care versus supportive care alone for
treatment of metastatic non-small cell lung cancer. J Natl Cancer Inst. 1993;85:794-800.
79. Quoix E, Dietemann A, Charbonneau J, et al. La chimiotherapie comportant du cisplatin est-elle utile dans le cancer bronchique non microcellulaire au stade IV?
Resultats d'une étude randomisée. Bull Cancer. 1991;78:341-346.
From the Ottawa Regional Cancer Centre, University of Ottawa, and the Ontario Cancer Treatment and Research Foundation, Ottawa, Ontario, Canada.
Address reprint requests to Dr Evans at the Ottawa Regional Cancer Centre, 501 Smyth Rd, Ottawa, Ontario, Canada, K1H8L6.