Even in a universal access health- care system
as exists in Canada, there are barriers to care for patients with
lung cancer. The reasons are undoubtedly multiple; one important
issue is the attitude of those physicians who must decide whether to
refer a patient with advanced lung cancer for consideration of
chemotherapy. Most care providers believe that the prognosis of
patients with advanced nonsmall-cell lung cancer is poor, and
many would not accept treatment themselves if they had this
disease. The survival of lung cancer patients is related to stage
at diagnosis, and at least one-third of Canadian patients present
with stage IV disease and another 25% to 30% have locally advanced
disease. The median survival for stage III nonsmall-cell
lung cancer is 9 to 14 months and for stage IV, 17 to 33 weeks. In
reality, even when the stage at presentation is advanced, current
therapies offer potential benefits by relieving cancer-related
symptoms and increasing survival.[4-10]
Multiple studies have shown symptomatic improvement in advanced
disease.[6-10] In addition, one randomized, controlled clinical
trial, incorporating a quality-of-life assessment, demonstrated a
significant improvement in quality of life for those patients who
received chemotherapy relative to those managed by best supportive
care alone.[10,11] These observations all suggest that patients
should at least be referred for consideration of treatment. Sometimes
a patient wont be referred because there is concern from
physicians, health-care administrators, and insurers about the cost
of treatment for advanced and incurable disease. The following
information summarizes the evidence for the benefit of systemic
therapy in metastatic (stage IV) nonsmall-cell lung cancer, and
then focuses on the cost and cost-effectiveness of chemotherapy for
stages III and IV disease. The data demonstrate that chemotherapy for
stage IV nonsmall-cell lung cancer and combined modality
therapy for stage III disease are cost-effective treatments that are
competitive with commonly used health care interventions.
There are now eight randomized controlled clinical trials of
cisplatin (Platinol)-based chemotherapy in comparison to best
supportive care.[10,12-18] Best supportive care has, in general,
consisted of the judicious use of radiotherapy in patients with
localized cancer-related symptoms, as well as the use of antibiotics
and steroids to control infections, cerebral metastases, and
hypercalcemia. Almost all of the trials have been small, with
approximately 20 to 50 patients per arm. Although the response rate
to chemotherapy in metastatic disease has generally been low (range
20% to 25%), there has been a small but consistent increase in median
survival time. Those patients receiving best supportive care
generally have had a median survival of only 17 weeks, whereas the
median survival of those who received chemotherapy has been
approximately 24 weeks. Several of the trials[10,12, 15,18] have
shown a statistically significant survival advantage. Four
meta-analyses have shown a reduction in the hazard ratio for death in
chemotherapy-treated patients [19-22]. As demonstrated in the
NonSmall-Cell Lung Cancer Collaborative Study, the overall
survival advantage at 1 year is 10% in absolute terms.
Five studies of chemotherapy in advanced nonsmall-cell lung
cancer have evaluated symptom improvement in patients undergoing
treatment.[6-10] The first of these, reported by Osoba et al in 1985,
used a regimen of bleomycin (Blenoxane), etoposide, and cisplatin and
yielded a 44% response rate, but a higher rate of symptom
improvement. Cough improved in 68% of patients, hemoptysis was
relieved in 78%, pain in 68%, dyspnea in 31%, and anorexia in 44%.
Subsequent studies by Ellis, Fernandez, Kris, Hardy, and
Thatcher have confirmed that chemotherapy yields symptomatic
improvement in 60% to 70% of patients.
Billingham has recently reported the results of a quality-of-life
study undertaken during a randomized comparison of MIC (mitomycin
[Mutamycin], ifosfamide [Ifex], cisplatin), compared to best
supportive care. Patients with metastatic disease completed
quality of life questionnaires using the European Organization for
Research and Treatment of Cancer (EORTC) quality-of- life core
questionnaire, as well as the lung module. There was a statistically
significant benefit in terms of quality-of-life in the
chemotherapy-treated patients over the first 6 weeks of the study.
With the evidence that chemotherapy produces a survival advantage as
well as symptomatic improvement and even benefit in the quality of
life of patients with advanced nonsmall-cell lung cancer,
resistance to the idea of offering systemic therapy to medically
appropriate patients has diminished. Nonetheless, there remain those
who believe that we cannot afford such treatment in a fiscally
constrained environment. The fiscal barrier appears to be the last
remaining barrier that needs to be dealt with to enable patients with
lung cancer to access the current best available care. An
understanding of what the costs of care are for patients receiving
lung cancer treatment is needed. In Canada, the Health Analysis
Modeling Group at Statistics Canada has undertaken a cost analysis of
the burden of care for common malignancies, including lung cancer.
These cost models are integrated into a microsimulation model of
Canadian health called the Population Health Model (POHEM).
The lung cancer component of the Population Health Model incorporates
information on histologic cell type (small-cell vs
nonsmall-cell), age, gender, and stage, coupled with clinical
algorithms of care and the survival appropriate for stage of disease.
It assigns costs according to tumor cell type and treatment options.
Multiple databases were accessed to develop the model including the
Canadian Cancer Registry at Statistics Canadas Health
Statistics Division. This database provided data on lung cancer
incidence, tumor cell type, and patient demographics.
Because staging information was not available from the Canadian
Cancer Registry, a retrospective staging study was undertaken by the
Alberta Cancer Board and the Ontario Cancer Registry. The stage
distribution of cases diagnosed between 1984 and 1985 was entered
into all Canadian nonsmall-cell lung cancer cases. The
treatment approaches incorporated into the model of care were those
identified from cancer registry data supplemented by responses from a
questionnaire sent to all Canadian thoracic surgeons and radiation
oncologists. From this information, estimates were made of the
proportion of patients who would be treated by a particular treatment approach.
The questionnaire was also used to estimate the average number of
treatment fractions and the total dose of radiation used on
radiotherapy patients, according to stage of disease. It was assumed
that patients with stage IV disease were managed by best supportive
care, as this has been the usual care provided to most patients in
Canada presenting with metastatic disease. At the time the model was
developed, it was estimated that only about 10% of patients with
stage IV nonsmall-cell lung cancer received chemotherapy in Canada.
Comparison of Hospitalization
Statistics Canadas 1992-1994 Person Oriented Hospital Morbidity
Information Database provided the duration of hospitalization for
diagnostic work-up and initial treatment for nonsmall-cell lung
cancer. Costs for hospital and outpatient chemotherapy treatment were
extracted from an economic analysis of a National Cancer Institute of
Canada Clinical Trial (BR.5), which compared chemotherapy vs best
supportive care in advanced nonsmall-cell lung cancer.
A record linkage study was performed in the province of Manitoba for
all patients diagnosed with lung cancer in 1990 (approximately 600)
to determine if the hospital utilization data from the BR.5 study
were still relevant. The study confirmed that patients with advanced
nonsmall-cell lung cancer who received chemotherapy used fewer
hospital bed days than those managed by best supportive care and that
the difference in the length of hospital stay was similar to that
observed in the BR.5 study.
1. Raby B, Pater J, Mackillop W: Does knowledge guide practice?
Another look at the management of non-small-cell cancer. J Clin Oncol
2. Evans WK, Will BP, Berthelot JM, et al: Estimating the cost of
lung cancer diagnosis and treatment in Canada: The POHEM model. Can J
Oncol 5:408-419, 1995.
3. Bunn PA: The treatment of non-small-cell lung cancer: Current
perspectives and controversies, future directions. Semin Oncol
21(suppl 6):49-59, 1994.
4. Lopez PG, Stewart DJ, Newman TE, et al: Chemotherapy in stage IV
(metastatic) nonsmall-cell lung cancer. Cancer Prevention
Control 1(1):18-27, 1997.
5. Okawara G, Rusthoven J, Newman, et al: Unresected stage III
nonsmall cell lung cancer. Cancer Prevention Control
6. Ellis PA, Smith IE, Hardy JR, et al: Symptom relief with MVP
(mitomycin C, vinblastine and cisplatin) chemotherapy in advanced
nonsmall-cell lung cancer. Br J Cancer 71:366-377, 1995.
7. Fernandez C, Rosell R, Abad-Esteve A, et al: Quality of life
during chemotherapy in nonsmall-cell lung cancer. Acta Oncol
8. Osoba D, Rusthoven JJ, Turnbull KA, et al: Combination
chemotherapy with bleomycin, etoposide, cisplatin in metastatic
nonsmall-cell lung cancer. J Clin Oncol 3:1478-1485, 1985.
9. Kris MG, Gralla RJ, Potanovich LM, et al: Assessment of
pretreatment symptoms and improvement after EDAM + mitomycin +
vinblastine (EMV) in patients with inoperable nonsmall-cell
lung cancer (NSCLC) (abstract 883). Proc Am Soc Clin Oncol 9:229, 1990.
10. Hardy JR, Nobel T, Smith RE: Symptom relief with moderate dose
chemotherapy (mitomycin C, vinblastine, cisplatin) in advanced
nonsmall-cell lung cancer. Eur J Cancer 60(5):764-766, 1989.
11. Cullen MH, Woodroffe CN, Billingham LJ, et al: Mitomycin,
ifosfamide and cisplatin (MIC) in nonsmall-cell lung cancer
(NSCLC):2. Results of a randomized trial in patients with extensive
disease (abstract 11). Lung Cancer 18(suppl 1):5, 1997.
12. Billingham LJ, Cullen MH, Woods J, et al: Mitomycin, ifosphamide
and cisplatin (MIC) in nonsmall-cell lung cancer (NSCLC):3.
Results of a randomized trial evaluating palliation and quality of
life (abstract 26). Lung Cancer 18(suppl 1):9, 1997.
13. Rapp E, Pater JL, Willan A, et al: Chemotherapy can prolong
survival in patients with advanced nonsmall-cell lung cancer:
Report of a Canadian multicentre randomized trial. J Clin Oncol
14. Woods RL, Williams CJ, Levy J, et al: A randomized trial of
cisplatin and vindesine versus supportive care only in advanced
nonsmall-cell lung cancer. Brit J Cancer 61:608-611, 1990.
15. Ganz PA, Figlin RA, Haskell CM, et al: Supportive care versus
supportive care and combination chemotherapy in metastatic
nonsmall-cell lung cancer. Does chemotherapy make a difference?
Cancer 63:1271-1278, 1989.
16. Quoix E, Dietemann A, Charbonneau J, et al: La chimioterapie
comportant du cisplatine est-elle utile dans le cancer bronchique non
microcellulaire au stade IV? Resultats dune etude
randomisée. Bull Cancer 78:341-346, 1991.
17. Kaasa S, Lund E, Thorud E, et al: Symptomatic treatment versus
combination chemotherapy for patients with extensive
nonsmall-cell lung cancer. Cancer 67:2443-2447, 1991.
18. Cellerino R, Tummarello D, Guidi F, et al: A randomized trial
alternating chemotherapy versus best supportive care in advanced
nonsmall-cell lung cancer. J Clin Oncol 9:1453-1462, 1991.
19. Cartei G, Cartei F, Cantone A, et al:
Cisplatin-cyclophosphamide-mitomycin combination chemotherapy with
supportive care versus supportive care alone for treatment of
metastatic nonsmall-cell lung cancer. J Natl Cancer Inst
20. Non-Small-Cell Lung Cancer Collaborative Group: Chemotherapy in
non-small cell lung cancer: A metaanalysis using updated individual
patient data from 52 randomized clinical trials. Br Med J
21. Grilli R, Oxman AD, Julian JA: Chemotherapy for advanced
non-small-cell lung cancer: How much benefit is enough? J Clin Oncol
22. Souquet PJ, Chauvin F, Boissel JP, et al: Polychemotherapy in
advanced nonsmall-cell lung cancer: A meta-analysis. Lancet
23. Marino P, Pampallona S, Preatoni A, et al: Chemotherapy vs
supportive care in advanced nonsmall-cell-lung cancer. Results
of a meta-analyses of the literature. Chest 106(3):861-865, 1994.
24. Thatcher N, Hopwood P, Anderson H: Improving quality of life in
patients with nonsmall-cell lung cancer: Research experience
with gemcitabine. Eur J Cancer 33(suppl 1):8-11, 1997.
25. Wolfson MC: POHEM a framework for understanding and modeling the
health of human populations. World Health Stat Q 47:157-176, 1994.
26. Jaakkimainen L, Goodwin PJ, Pater J: Counting the cost of cancer
chemotherapy in the National Cancer Institute of Canada randomized
trial of nonsmall-cell lung cancer. J Clin Oncol 8:1301-1309, 1990.
27. Statistics Canada: Hospital Statistics: Preliminary Annual
Report, 83-241, 1992-1993, Ottawa, Canada: Government of Canada,
Supply and Service, Ottawa, Canada.
28. Hull RD, Hirsch J, Sackett DL, et al: Cost-effectiveness of
primary and secondary prevention of fatal pulmonary embolism in
high-risk surgical patients. Can Med Assoc J 127:990-995, 1982.
29. Goodwin PJ, Feld R, Evans WK, et al: Cost-effectiveness of cancer
chemotherapy: An economic evaluation of a randomized trial in
small-cell lung cancer. J Clin Oncol 6:1537-1547, 1998.
30. Wodinsky H, Jenkin RDT: The cost of radiation treatment at an
Ontario cancer centre. Can Med Assoc J 137:906-909, 1987.
31. Laupacis A, Feeny D, Detsky AS, et al: How attractive does a new
technology have to be to warrant adoption of the utilization?
Tentative guidelines for using clinical and economic evaluation. Can
Med Assoc J 146:77-84, 1992.
32. Bonomi P, Kim K, Cheng A, et al: Phase III trial comparing
etoposide (E) and cisplatin (C) versus Taxol (T) with
cisplatinG-CSF (G) versus Taxol-cisplatin in advanced
nonsmall-cell lung cancer. An Eaastern Cooperative Oncology
Group (ECOG) trial (abstract 1145). Proc ASCO 15:382, 1996.
33. Dillman RO, Seagren SI, Propert KJ, et al: A randomized trial of
induction chemotherapy plus high-dose radiation versus radiation
alone in stage III nonsmall-cell lung cancer. N Engl J Med
34. Evans WK, Will BP, Berthelot JM, et al: The cost of combined
modality interventions for stage III nonsmall-cell lung cancer.
J Clin Oncol 15:3338-3348, 1997.
35. Kris MG, Martini N, Gralla RJ, et al: Primary chemotherapy in
stage IIIA nonsmall-cell lung cancer patients with clinically
apparent mediastinal lymph node metastases: Focus on 5-year
survivors. Lung Cancer 9:369-376, 1993.
36. Burkes RL, Ginsberg RJ, Shepherd FA, et al: Induction
chemotherapy with MVP (mitomycin C + vinblastine + cisplatin) for
stage III (T1-3, N2, M0) unresectable nonsmall cell-lung
cancer. The Toronto experience. Lung Cancer 9:377-382, 1993.