Chemotherapy
The Role of Chemotherapy in
Non-Small Cell Lung Cancer

By Elizabeth Johnson, MD
 

Palliative chemotherapy

Chemotherapy might be called palliative if it accomplishes one or more of the following goals: increases duration of survival, reduces symptoms from the disease, or improves quality of life (the last two not necessarily synonymous). Patients with metastatic lung cancer, or those with locally advanced disease not amenable to curative interventions are potential candidates for this approach. The value of each or any of these gains needs to be weighed against the "cost" in terms of toxicity experienced by the patient, and financial impact incurred by the patient and by society.

Survival duration (quantitative assessment)

The first substantiation of an impact on survival duration by chemotherapy compared to best supportive care (BSC) was published in 1988.¹ A subsequent meta-analysis confirmed this benefit, as seen in Figure 1.² These publications, both assessing suboptimal chemotherapy by today's standards, describe the benefit in terms of increase in median survivals of 1.5 to 3 months.^1,2 On initial consideration, this increase hardly seems worth the toxicities of chemotherapy. However, several points need to be considered. First, with an expected median survival time without treatment of 6 months, the improvement represents a 25-50% increase in survival time. Second, although the average increase in median survival is measured in a few months, this benefit is not evenly distributed over all recipients of chemotherapy. While many people receive no benefit at all (and some even suffer a shortened survival time), some patients incur substantial increases in survival of even 1-2 years more than expected. The best way to illustrate this finding is to assess the survivorship at 1 and 2 years. At one year, the meta-analysis found 15.1% of BSC patients alive compared to 23.6% of chemotherapy patients. Results of modern chemotherapy as assessed in a more recent multicenter trial³ can be illustrated by superimposing results on the meta-analysis survival curves, as seen in Figure 2. The overall median survival of patients in this study was 8 months, the 1-year survival was 34%, and the 2-year survival was 12%. With currently available chemotherapy, 35% of patients can expect to be alive at one year and 12-15% at two years compared to 15% and 5% respectively with best supportive care.
 

Figure 1.  Survival in trials of supportive care versus supportive care plus chemotherapy (only trials using regimens based on cisplatin): meta-analysis curves.	Figure 2.  Meta-analysis survival curves with superimposed data points from ECOG 1594[3] (circle denotes median survival; asterisk denotes one-year survival, diamond denotes two-year survival.

Survival duration (patient-related assessment)

Only limited data exist on patient preferences for palliative chemotherapy primarily to extend survival time. In one study, only 22% of patients chose chemotherapy for an extension of 3 months, although thresholds for acceptance varied widely from 1 week to more than 24 months.⁴ A second study found that patients anticipating a 6 month survival were 2.6 times more likely to favor life-extending therapy over comfort care.⁵ Generalizations about patient preferences cannot necessarily be applied to an individual patient, and the value of the possible extra survival time must be judged by the patients themselves.

Improvement in symptoms

Few trials have assessed symptom relief as an endpoint. One such study of mitomycin C, vinblastine and cisplatin (MVP) resulted in complete or substantial improvement in tumor related symptoms in 69% of patients.⁶ Descriptive trials suggest that lung cancer related symptoms such as cough, chest pain, dyspnea, fatigue and hemoptysis are reduced in 30-50% of patients.⁷ A trial of docetaxel vs. BSC did show a reduction in opiate and non-opiate analgesic use, fewer tumor related medications other than for pain and less palliative radiation therapy in the treatment arm.⁸

One study of patient preferences surveyed advanced stage lung cancer patients who had previously received platinum-based chemotherapy; 68% said they would choose chemotherapy if it would substantially reduce symptoms without prolonging life.⁴

Quality of life (QOL)

Few trials compare QOL of platinum regimens vs BSC. Two such trials found improvement in QOL scores in platinum-containing chemotherapy arms compared to the BSC arms.^9,10 As shown in Table 1, recent studies of single agents compared to BSC almost universally show an improvement in QOL. ^8,11-13 QOL is more frequently incorporated into modern studies, especially if the regimens being tested are likely to be fairly close in efficacy.

Patient-perceived QOL may be influenced by a sense of doing something active against the disease, or by the desire to avoid the toxicity of chemotherapy, even if survival is somewhat shortened.

 

Table 1.
Author	Agent	No of pts	Schedule	Suvival	Quality of Life (QOL)
ELVIS group	Vinorelbine	191	D1,8, q 21 days	28 vs. 21 wks p=0.03	Fewer lung cancer-related symptoms; worse toxicity related symptoms, better QOL scores with vinorelbine
Anderson	Gemcitabine	302	1000mg/m2 D1, 8, 15, q 28 days	4 vs. 4 mo p=NS	Sustained improvement in 22% vs 9% favoring gemcitabine
Ranson	Paclitaxel	157	30 IV q 3 week	6.8 vs. 4.8 mo p=0.048	Functional activity score better with paclitaxel, other scores similar
Roszkowski	Docetaxel	207	100mg/m2	28 vs. 15% at 1 yr p=0.026	Improvement in clinical symptoms; QOL in favor of docetaxel

Cost

The cost of therapy is an important consideration. Cost studies have indicated that palliative chemotherapy would seem to be appropriate. Data from an early prospective randomized trial in Canada suggests that chemotherapy is not significantly more costly than BSC and may be less since patients receiving BSC required more palliative radiation therapy to relieve symptoms.¹⁴ More modern chemotherapy is arguably more costly. An assessment of the total costs of medical care for up to 24 months after initiation of treatment with cisplatin/vinorelbine and carboplatin/paclitaxel was $40,292 and $48,940 respectively.¹⁵ In terms of cost per year of life gained, estimates generally range between $5000 and $30,000.^14,16

Patient selection

Which patients are most likely to benefit from chemotherapy and thus should consider the risks involved? Currently, we can predict lack of benefit for some groups. Those with ECOG/Zubrod performance status of 3 or 4 (see Table 2) never show response and should never be treated with chemotherapy. Patients with PS 2 have a lower rate of response and shorter survival times and higher toxicity than PS 1 and 0. Chemotherapy may still be considered in this group, but the risk-benefit ratio of platinum-based chemotherapy is considerably higher.¹⁷

 

Table 2.
ECOG/Zubrod Scale	Performance Status	Karnofsky Score
0	Asymptomatic and fully active	100%
1	Symptomatic; fully ambulatory; restricted in physically strenuous activity	80-99%
2	Symptomatic; ambulatory; capable of self-care; more than 50% of waking hours are spent out of bed	60-79%
3	Symptomatic; limited self-care; spends more than 50% of time in bed, but not bedridden	40-59%
4	Completely disabled; no self-care; bedridden	20-39%

Which chemotherapy regimen?

Platinum regimens (cisplatin or carboplatin plus a taxane, gemcitabine or vinorelbine) are currently most extensively studied in trials and are generally considered standard for patients with good performance status. Even fit elderly patients obtain anticipated benefits from these regimens.¹⁸ A recently presented study comparing carboplatin and paclitaxel to single agent paclitaxel showed superiority of the platinum combination.¹⁹ This advantage also extended to patients with PS 2. At least two studies have shown equivalence of a non-platinum doublet (two-drug combination) to platinum regimens.^20,21 Other comparisons of non-platinum doublets have not always shown equivalence and toxicity is not always less. Further work is needed in this area before this approach becomes standard. Finally, single agent therapy with navelbine, gemcitabine, paclitaxel or docetaxel has been shown to offer some survival advantage over BSC in a number of trials,^8,11-13 and is appropriate to consider in the elderly and those who wish to avoid platinum therapy.

Curative chemotherapy

Treatment can be said to contribute to cure if its application results in an increase in the percentage of patients alive and disease free at five years. Chemotherapy has the potential to increase the cure rate of localized disease in two settings: in conjunction with radiation therapy in locally advanced disease and as an adjuvant to surgery.

Locally advanced disease

Multiple prospective randomized trials have now shown that combination chemotherapy and radiation therapy can offer a cure (disease-free survival at 5 years) for a very limited group of patients.^22-24 The cure rate is generally between 10-15%. The meta-analysis also clearly supports the addition of chemotherapy even taking into account older regimens and suboptimal radiation.² Even in those patients not attaining a cure, the addition of chemotherapy does add to survival time as has previously been shown in metastatic cancer.

Patient selection is even more important in this setting than in palliative chemotherapy. The majority of the positive trials excluded patients with PS 2 or less, those with pleural effusions or supraclavicular lymph nodes, and those with weight loss greater than 5 % of baseline. Application of the toxic combination therapy in these groups of patients may not be warranted since phase III data is not yet available to support its benefit. A randomized trial of combination chemotherapy/radiation vs. radiation alone in PS2 patients was led by the Radiation Therapy Oncology Group (RTOG 9701) and results are pending.

All positive studies have included platinum-based therapy. Recent data indicate that concomitant application of chemotherapy and radiation is superior to sequential administration.^25,26

Assessments of patient preference have shown a great variability in the improvement thresholds for which patients were willing to consider more toxic treatments. These thresholds were generally lower than those identified by nurses and radiation technicians.²⁷

Adjuvant Therapy
 

Multiple attempts to define a survival advantage with the addition of post operative chemotherapy to surgical resection in Stages I through IIIA have yielded variable results, none of which are convincing. The best assessment of benefit again comes from the meta-analysis conducted of seventeen randomized trials of adjuvant chemotherapy vs observation.2 The trials assessing the older alkylating agent combinations showed a clear detriment to survival from the addition of chemotherapy. However, pooling of the data from the eight platinum containing protocols showed a trend toward improvement in survival with an absolute improvement of 3% (95% CI: -0.5% to7%) at 2 years and 5 % (95% CI: -1% to 10%) at 5 years (see Figure 3). Despite this trend, postoperative adjuvant chemotherapy cannot be considered standard at this time.

Criticisms of available trials include inadequate statistical power, older chemotherapeutic regimens, and poor patient compliance with resultant inadequate chemotherapy delivery in the treatment arms. Studies using adequate numbers of patients and more modern chemotherapy and supportive care regimens are currently underway in English, European, Canadian, Italian and American cooperative groups.

In two prospective randomized trials, adjuvant chemotherapy delivered pre-operatively (neo-adjuvant therapy) has been questionably demonstrated to increase survival in patients with Stage IIIA (mediastinal node) disease.^28,29 Both of these trials were stopped early when monitoring committees identified superiority of the treatment arm. This finding has held up in longer-term analysis.²⁹ Each study had problems related to outcomes in either the treatment arm or the control arm being markedly different than expectations. One trial was imbalanced in at least one prognostic factor.²⁸ Despite lingering questions, additional trials addressing this question are unlikely to be conducted in the United States. Accrual in a similar trial led by the Cancer and Leukemia Group B (CALBG) was suddenly halted once results of these studies became known.

Given the benefit of chemotherapy seen in other stages of non small cell lung cancer, application in the pre-operative setting for stage IIIA disease is not unreasonable. However, similar benefits should only be anticipated in patients who would have been eligible for these two trials. Specifically, patients should have minimal mediastinal nodal disease discovered at the time of mediastinoscopy. Those with bulky mediastinal nodes were not included in these studies and may not benefit from this approach. They might be better served by a chemotherapy/radiation program.

The application of pre-operative chemotherapy in earlier stage lung cancer is currently under investigation. Single arm studies have demonstrated the feasibility and lack of increased operative morbidity/mortality.³⁰ Phase III trials of preoperative chemotherapy are now underway.

Conclusion

In summary, chemotherapy has established roles in the palliation of advanced disease and in the enhancement of outcome with radiation therapy in locally advanced disease. Patient preferences should play a strong role in the decisions to employ chemotherapy. In the operative setting, the role of adjuvant therapy is still under investigation and should not be employed routinely. In the future, hopefully the outcome for all patients with established lung cancer will improve as a result of current research into biological therapies for this disease.

References

[Source note: Figures 1, 2, and 3 reproduced here with permission of the British Medical Journal Publishing Group from BMJ 1995; 311:906 Figure 8 and BMJ 1995; 311:901 Figure 2]

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