Nonsmall-cell lung cancer, including squamous cell, adeno and large-cell carcinomas, accounts for approximately 80% of lung cancers; its 5-year survival rate is about 12% across all stages. The median survival duration in metastatic nonsmall-cell lung cancer, however, which constitutes approximately 60% of all nonsmall-cell lung cancer cases, is around 6 months, and the 1-year survival rate ranges between 10% and 20%.
Chemotherapy is by far the most widely used treatment for advanced nonsmall-cell lung cancer, but survival has been only marginally improved, even with the use of modern cisplatin(Drug information on cisplatin) (Platinol)-based regimens. Meta-analyses of randomized clinical studies in patients with metastatic nonsmall-cell lung cancer comparing chemotherapy to best supportive care have recently shown marginal benefits of cisplatin-based regimens on survival and on quality-of-life improvement.[2,3]
One of the meta-analyses suggests that cisplatin-based chemotherapy may provide a 27% reduction in the risk of death and an absolute benefit of about 10% at 1 year in metastatic disease. Because of this really modest benefit, it has become mandatory to evaluate the toxicity of chemotherapy regimens and their impact on patients quality of life.
Quality of life may be improved with chemotherapy for patients with unresectable stage III and stage IV disease, but data to support this supposition are sparse.[4-6] Evidence documenting symptomatic improvement that supports a palliative role for chemotherapy in nonsmall-cell lung cancer is principally derived from retrospective reviews of patients and physicians perception or, when prospectively derived, is not obtained from randomized trials in which some patients received no therapy.[4,7] Furthermore, balancing symptomatic improvement related to treatment with the toxicities caused by chemotherapy can be difficult.
A number of new chemotherapeutic agents with innovative mechanisms of action have recently become available in clinical practice. These novel compounds, such as paclitaxel(Drug information on paclitaxel) (Taxol), docetaxel (Taxotere), vinorelbine (Navelbine), gemcitabine(Drug information on gemcitabine) (Gemzar), and irinotecan(Drug information on irinotecan) (CPT-11; Camptosar) have shown activity as single agents. They have also been tested in combination with platinum compounds in phase II trials in nonsmall-cell lung cancer showing promising efficacy with a relatively low toxicity profile.
Paclitaxel has been shown to be one of the most active agents in nonsmall-cell lung cancer. In phase II trials conducted by the Eastern Cooperative Oncology Group (ECOG) and at M. D. Anderson Cancer Center, paclitaxel as a single agent yielded response rates of 21% and 24%, with 1-year survival rates of 30% and 40%, respectively.[9,10] The combination of paclitaxel with cisplatin improved the response rate (range, 35% to 38%) in some phase II studies including a small number of patients.[11,12]
More importantly, quality-of-life improvement could be a possibility when using these combinations because of their safety profile. Of course, before any generalized conclusion can be made, such an improvement should be demonstrated in phase III randomized trials in which quality of life represents an important end point, and the evaluation is formally requested through a validated instrument.
Two phase III trials of platinum/paclitaxel combinations reporting quality-of-life evaluation trials have recently been published.[13,14]
In the ECOG trial, the standard therapy for nonsmall-cell lung cancer (cisplatin [75 mg/m²]/etoposide [VP-16] [100 mg/m², days 1 through 3]) was compared with the experimental arms containing two dose levels of paclitaxel (135 mg/m² and 250 mg/m² in 24 h) combined with cisplatin (75 mg/m²). In 560 eligible patients with stage IIIB and IV disease, the response rate, median survival time in months, and 1-year survival were 12%, 7.69 months, and 31.6% for the standard regimen; 26.5%, 9.56 months, and 36.9% for the low-dose paclitaxel regimen; and 32.1%, 9.99 months, and 39.1% for the high-dose paclitaxel regimen, respectively. These results show a significantly higher response rate for the paclitaxel-containing regimens, together with a trend for longer survival.
In the Eastern Cooperative Oncology Group trial, quality of life was evaluated using the Functional Assessment of Cancer TherapyLung (FACT-L) assessment scale at baseline, 6 weeks, 12 weeks, and 6 months. Subscale scores for physical, functional, emotional, and social well-being, plus a score of lung cancer symptoms, were also recorded. Despite some improvement of quality of life in the paclitaxel-containing arms, the conclusion was that, on all scores, there were no treatment arm differences, despite increased myalgias and neurotoxicities on the paclitaxel-containing arms.
The European Organization for Research and Treatment of Cancer (EORTC) study compared the combination of cisplatin (80 mg/m²) and teniposide(Drug information on teniposide) (VM-26; Vumon) (100 mg/m² x 3) (Arm A) which was, at that time, the standard of the group, with the cisplatin/paclitaxel (175 mg/m², 3-hour infusion) (Arm B) regimen in 132 patients with stage IIIB or IV disease. Response rates were 44% in the paclitaxel arm and 30% in the teniposide arm, whereas survival was almost the same (9.4 and 9.7 months, respectively).
Selected centers participated in quality-of-life assessment, which was performed by the EORTC Quality of Life Questionnaire (QLQ)-C30, and the lung module, administered at baseline and every 6 weeks thereafter. Arm A achieved a better score at week 6 for emotional, cognitive, and social functioning; global health status; fatigue; appetite loss; and hair loss (which was still partially maintained at 12 weeks). Arm B attained a better score for cough, and tingling in the hands and feet. The authors conclusions were that the paclitaxel-containing regimen appeared to be superior in response rate, side effects, and quality of life, although median survival did not seem to be improved.
Ongoing Trials Evaluating Quality of Life
Other trials comparing paclitaxel-containing regimens and evaluating quality of life are still ongoing. In some of these trials, cisplatin has been replaced by carboplatin(Drug information on carboplatin) (Paraplatin) because of the frequent findings of myalgia and peripheral neurotoxicity in the cisplatin/paclitaxel combination, due to the overlapping neurotoxicity of the two drugs. The combination of carboplatin and paclitaxel was tested in many phase II trials with different infusion times for paclitaxel (24 hours, 3 hours, 1 hour).[17-19] Dose-limiting toxicity was myelosuppression with 24-h infusion and neuropathy with shorter infusions.
Response rates ranged from 12% to 62%, and 1-year survival was 54% for patients treated at the Fox Chase Cancer Center. On the basis of these data, the carboplatin/paclitaxel regimen was included in some large cooperative trials ongoing in the United States (Southwest Oncology Group [SWOG]) and in Europe (EORTC, Italian Lung Cancer Project), and in evaluating quality of life. The SWOG study is comparing the combination of cisplatin/vinorelbine vs the carboplatin/paclitaxel regimen in 400 patients. The Italian Study is a three-arm study evaluating the standard cisplatin/vinorelbine vs the new combinations cisplatin/gemcitabine and carboplatin/paclitaxel. The planned accrual is 600 patients at more than 40 participating centers. Quality of life is being evaluated with the EORTC Quality of Life Questionnaire-C30. Another of these trials, the PAN-European Trial (BMS-271), comparing paclitaxel (200 mg/m², 3-hour infusion) plus carboplatin (area under the concentration-time curve of 6 [AUC in mg/mL · min]) vs paclitaxel plus cisplatin (80 mg/m²), completed the accrual of 618 patients in July 1997 and its results are eagerly awaited.
Despite the discovery of new active drugs and the improved response rates, overall survival is only slightly better than in the recent past, and, as a consequence, it is of fundamental importance to evaluate the toxicity of a given therapy and its impact on the quality of life of treated patients. Standard end points do not measure the effects of cancer or its treatment on the emotional, spiritual, and social dimensions of patients lives. The use of a quality-of-life instrument may help in determining a patients preference for treatment.
In the past, there were few formal studies of quality of life in patients with nonsmall-cell lung cancer. In a randomized comparative trial of chemotherapy and radiotherapy, using a patient-rated psychological scale, results indicated that patients are willing to trade toxicity for the chance of responding to treatment. No differences in quality of life were detected in the follow-up period in patients treated with radiotherapy or with platinum-based chemotherapy.
Unfortunately, gathering data from properly validated questionnaires on quality of life is very time-consuming, and there are considerable difficulties in the methodology for analyzing the data. Nevertheless, there are now several instruments to measure quality of life such as the FLIC, the FACT-L, and the newer EORTC QLQ-C30 and lung cancer module questionnaire described previously.
Though they are far from being ideal questionnaires, the ECOG and EORTC trials used two of the better validated instruments. The ECOG study could not demonstrate a significant difference in quality of life among the three arms, though a short-lived improvement in quality of life was more frequent in the paclitaxel arms.
An interesting finding of the ECOG study was that the use of FACT Physical Well-being, and FACT Trial Outcome Index (which combines the physical, functional, and lung cancer scores) can predict response and survival. This confirms the earlier propositions that quality of life can be considered an independent prognostic variable for survival in lung cancer.[23,24]
The EORTC study presents some limitations regarding the validity of the quality-of-life assessment. In fact, quality of life was evaluated in a limited number of patients (104/317) because only a few centers decided to participate. Besides, the reference regimen (cisplatin-teniposide) cannot be considered the best standard outside the specific experience of the group. Finally, there was a consistent dropout in serial assessment of quality of life (104 down to 32 patients from baseline to 24 weeks).
This consistent dropout is a difficulty that researchers are facing in almost every study. Reasons for this can be the worsening of the patients symptoms, the lack of motivation by the investigators, and also the lack of a dedicated staff member or team for quality-of-life evaluation. This could result in difficulties in explaining the procedures and in collecting quality-of-life data in order to optimize completeness and reduce variability and noncompliance.
Despite these problems, some large ongoing trials contain a formal quality-of-life-evaluation, and some include a pharmacoeconomic analysis. It is to be hoped that through the interweaving of the results of such trials (or the confirmation of activity in different settings and situations, similar trends in toxicity, and quality of life), a standard therapy can be identified. Also, when determining the balance between quality and quantity of life, the patients views should always be considered. Patients generally believe that small improvements in survival are worthwhile, despite the perceptions among medical and nursing staff of toxic chemotherapy. The support of appropriate clinical studies represents the only valid way of improving the outlook of patients in order to develop and confirm the benefits of new treatments for advanced nonsmall-cell lung cancer.