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Japanese Journal of Clinical Oncology Pages 749-753

Quality of Life (QOL) Assessment of MIP (Mitomycin, Ifosfamide and Cisplatin) Chemotherapy in Advanced Non-small Cell Lung Cancers (NSCLC)
Introduction
Materials And Methods
   Quality of Life Assessment
   Statistical Methods
Results
   Patient Characteristics
   Response
   Toxicity
   Change of QOL
   Overall Survival
Discussion
Acknowledgment
References
Quality of Life (QOL) Assessment of MIP (Mitomycin, Ifosfamide and Cisplatin) Chemotherapy in Advanced Non-small Cell Lung Cancers (NSCLC)

Quality of Life (QOL) Assessment of MIP (Mitomycin, Ifosfamide and Cisplatin) Chemotherapy in Advanced Non-small Cell Lung Cancers (NSCLC)

Ji-Youn Han1, Hoon-Kyo Kim1, Byung Gil Choi2, Hanlim Moon1, Young Seon Hong1 and Kyung Shik Lee1

Departments of 1Internal Medicine and 2Radiology, College of Medicine, the Catholic University of Korea, Catholic Cancer Center, Seoul, Korea

Background: Quality of life (QOL) assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival in cancer patients.
Methods: From July 1995 to February 1997, 38 symptomatic patients with advanced non-small cell lung cancer (NSCLC) were treated with MIP chemotherapy (mitomycin 6 mg/m2, ifosfamide 3000 mg/m2 and cisplatin 50 mg/m2 on day 1 every 3 weeks). Patients were assessed for QOL including physical well-being, general symptoms and lung cancer-specific symptoms, as well as objective response.
Results: The overall response rate was 38.9% (14/36, all were partial response) and the median duration of response was 3.5 months [95% confidence interval (CI) 2.0-4.0]. The median duration of overall survival was 7 months (95% CI 5.9-8.5). The overall improvement of QOL was 58.3% with 21 patients feeling better on treatment. The toxicity of chemotherapy was mild, mainly nausea/vomiting and minimal alopecia. Using multiple clinical predictors of survival (age, histology, stage, performance status), only change of QOL emerged significantly (P = 0.0007).
Conclusions: MIP had an endurable response and low toxicity profile, and provided good QOL. Integral QOL data in our study provided the strong prediction of survival in advanced NSCLC. Further experienced QOL study will provide greatly enhanced outcome data in clinical trials.

Key words: non-small cell lung cancer - quality of life - MIP treatment - L.A.S.A. scales

INTRODUCTION

The role of chemotherapy is still controversial in advanced non-small cell lung cancers (NSCLCs) due to the fact that prolonged survival is dismal in these groups. Given this fact, palliation of symptoms is a major goal of management and radiation therapy plays an important role in this regard. Over the past decade, combination chemotherapies, most containing cisplatin, have produced higher response rates and improved survival (1-4). However, the survival benefit is clearly modest and complete responses are rare; there is a need to balance the benefit gained in terms of symptomatic improvement against toxicity of chemotherapy and the purpose of quality of life (QOL) assessment is to measure and quantify this balance (5-7). In response to this awareness, a number of disease-specific QOL instruments have been developed in recent years (9-12). Assessment of QOL of cancer patients in clinical trials is generally composed of two basic elements: a core QOL questionnaire covering general aspects of health-related QOL, and additional disease- or treatment-specific questionnaires.

MIP (mitomycin, ifosfamide and cisplatin) is composed of three active agents for NSCLC. With moderate-dose cisplatin (50 mg/m2), it is tolerable without serious toxicity (13). In this paper, we report the QOL assessment, including health-related QOL and disease-specific symptoms, in advanced NSCLC to address the importance of QOL in the prediction of response to and survival with MIP chemotherapy in advanced lung cancer patients.

MATERIALS AND METHODS

Patients with histologically or cytologically documented inoperable NSCLC were eligible for entry to this trial. Additional eligibility criteria included the following: measurable and/or assessable lesions, age less than 75 years, Eastern Cooperative Oncology Group (ECOG) performance status less than three, and adequate bone marrow reserve, liver and renal functions, and a life expectancy of more than three months. No prior chemotherapy and/or radiotherapy were allowed. Furthermore, suitability for follow-up evaluation and informed consent were required. Patients with symptoms or signs considering palliative radiation therapy, such as brain metastasis, painful bone metastasis, bronchial obstruction or massive hemoptysis, were excluded.

Before study entry, patients were evaluated by physical examination, laboratory tests including blood counts, blood chemistries, urinalysis, chest X-ray, ECG, bone scan, and computed tomography (CT) scan of the chest. Before every cycle of chemotherapy, chest X-ray, blood counts and blood chemistries were performed. CT scan of the brain was not routinely required, but was performed in the presence of neurological symptoms.

All patients received the following combination chemotherapy: mitomycin (6 mg/m2), ifosfamide (3000 mg/m2) and cisplatin (50 mg/m2) intravenously on day 1. The regimen was repeated every three weeks and continued until progression of disease, fall in performance status, or to a maximum of six cycles. On progression, no restrictions were posed on secondary treatments.

Standard World Health Organization (WHO) criteria for response and toxicity assessment were used. The response to chemotherapy was evaluated after every second cycle of chemotherapy. Patients were assessable for toxicity after at least one course of chemotherapy and for response after at least two courses, unless rapid progression of the disease was evident earlier. Patients were monitored until death or until the time analysis. The duration of response and survival were calculated from the date of entry onto this trial.

Quality of Life Assessment

Patients' self-evaluation of QOL comprised 10 linear analog self-assessment (L.A.S.A.) scales (15) that measure feeling of well-being, mood, level of activity, pain, nausea and vomiting, appetite, and lung cancer-specific symptoms such as coughing, sputum, hemoptysis and dyspnea. For a given variable, a 10 cm line is drawn, and the ends of the line are labeled with words descriptive of extremes of that symptom. The patients were asked to mark each line to indicate their feelings at that moment; the distance, in centimeters, along the line to the mark gives a score out of 10, the sum of all variables giving a score out of 100. Each L.A.S.A. form was completed immediately before treatment and then every six weeks. Then the changes in patients' L.A.S.A. scores during treatment were compared with their objective response. We used the original English version of the questionnaire interpreted in Korean.

Statistical Methods

Overall survival was estimated by the Kaplan-Meier product limit method. The log-rank test was used to calculate statistical significance in univariate analysis, and Cox's proportional hazard method was used for multivariate analysis. Changes in QOL scores were compared by Student's t-test. Differences in response rate between patients with different ages, histologies and clinical stages were analyzed by using Fisher's exact test or [chi]2 test.

RESULTS

Patient Characteristics

Between July 1995 and February 1997, 38 patients were entered into the study and 36 were evaluable for response and toxicity. Two patients were excluded from the analysis because they refused further treatment after the first cycle of chemotherapy. The characteristics of all patients are summarized in Table 1. The majority of patients were male (78.9%) and had good performance status (PS) equal to or less than one (by ECOG) (73.7%). A total of 116 cycles were delivered with a median of three (range 1-7 cycles) per patient. The median duration of follow-up was seven months (range 2-23 months).

Response

No patients obtained a complete response (CR) and 14 patients obtained a partial response (PR) for an overall response rate of 38.9%. The median duration of response was 3.5 months (range: 2.0-4.0 months, 95% CI). No significant difference in terms of response was noted between differing age, histology, clinical stage or baseline QOL (Table 2).

Table 1. Patients' characteristics
Characteristic Numbers
Patients entered 38
Patients assessable 36
Age (median) 33-76 (60) years old
Sex M:F = 30:8
Performance status (by ECOG)
   0 6
   1 22
   2 10
Histology
   Squamous cell 19
   Adenocarcinoma 17
   Poorly differentiated carcinoma 2
Stage
   IIIB 19
   IV 19
Cycle of chemotherapy 1-7 (median 3)
Follow-up (months) 2-23 (median 7)

Table 2. Response according to patients' characteristics
Characteristic No. Response P value
PR NC PD %PR
Histological subtype
   Adenocarcinoma 17 6 7 4 35.3 0.5
   Squamous 17 8 4 5 47.1  
   Poorly differentiated 2 0 1 1 -  
Clinical stage
   IIIB 19 9 6 4 47.4 0.2
   IV 17 5 6 6 29.4  
Age
   <60 17 5 6 6 29.4 0.2
   [ge]60 19 9 6 4 47.4  
Baseline QOL
   High QOL ([ge]50) 7 4 2 1 57.1 0.2
   Low QOL (<50) 29 10 10 9 34.5  
Overall 36 14 12 10 38.9  
PR, partial response; NC, no change; PD, progressive disease.

Table 3. Non-hematological toxicity
Toxicity Toxicity grade (WHO)
0 1 2 3 4
Infection 31 (86.1%) 3 (8.3%) 2 (5.6%) 0 0
Nausea/vomiting 7 (19.4%) 24 (66.7%) 4 (11.1%) 1 (2.8%) 0
Mucositis 36 (100%) 0 0 0 0
Diarrhea 36 (100%) 0 0 0 0
Alopecia 16 (44.5%) 17 (47.2%) 3 (8.3%) 0 0
Neuropathy 29 (80.6%) 7 (19.4%) 0 0 0
Constipation 23 (63.9%) 13 (36.1%) 0 0 0
Rash 34 (94.4%) 2 (5.6%) 0 0 0

Table 4. Hematological toxicity
Toxicity Toxicity grade (WHO)
0 1 2 3 4
Anemia 18 (50.0%) 15 (41.7%) 3 (8.3%) 0 0
Leukopenia 29 (80.6%) 0 7 (19.4%) 0 0
Thrombocytopenia 32 (88.8%) 2 (5.6%) 2 (5.6%) 0 0

Toxicity

Toxicity was generally mild and consisted principally of nausea and vomiting. One patient (2.8%) had severe nausea and vomiting, and six patients (16.7%) had no nausea and vomiting. For the remainder, toxicity was mild (Table 3). Hematological toxicity, calculated at the nadir, was mild and no patient experienced greater than grade two myelosuppression. There was no dose reduction or delay due to toxicity (Table 4).

Change of QOL

Twenty-one (14 with PR, five with no change and two with progressive disease) of 36 patients (58.3%) reported improvement of QOL during chemotherapy. Fourteen patients who had an objective response to chemotherapy had a significant improvement in their L.A.S.A. scores during treatment (P < 0.01). Those patients who showed no objective response to chemotherapy showed no significant change in their L.A.S.A. scores (P > 0.05) (Fig. 1). Among L.A.S.A. scales, feeling of well-being and lung cancer-specific symptoms were mostly improved.


Figure 1. L.A.S.A. scores of patients before and after MIP chemotherapy.

Compliance with the protocol diminished with the course of chemotherapy. Although the assessment of QOL was available in all patients at baseline and six weeks, it was only available in 10 and five patients at 12 and 18 weeks, respectively.

Overall Survival

The median survival was seven months (range: 5.9-8.5 months, 95% CI) and survival at one year was 37.9% [standard error (SE), 12.7%]. During follow-up, 17 patients died due to the progression of disease (16 patients) and sepsis not related to treatment (one patient). Change of QOL from baseline to the subsequent six week assessment correlated highly with survival (correlation coefficient 0.61); we therefore placed patients into two groups, those with QOL improvement (n = 21) and those without QOL improvement (n = 15), and evaluated the prognostic value for survival with other multiple clinical factors (age, histology, clinical stage, PS). Univariate analysis of prognostic variables for overall survival showed that change of QOL and age were statistically significant (P = 0.003 and 0.005, respectively). In multivariate analysis, only change of QOL was significant (P = 0.0007) with an estimated relative risk of 2.7 for patients without QOL improvement (Table 5).

Table 5. Predictors for survival
Analysis P value
Univariate
   Age 0.005*
   Sex 0.10
   Histology 0.08
   Stage 0.3
   Performance status (PS) 0.24
   Change of QOL 0.003*
Multivariate
   Change of QOL 0.0007*

DISCUSSION

Because of the complex relationship between treatment benefit and toxicity, careful measurement and documentation of patients' functional status has become a necessary component of outcome evaluation in many clinical trials (5-7).

QOL assessment has emerged to measure and quantify the balance between treatment benefit and toxicity, and has a value in predicting response and overall survival (7,8).

Advanced lung cancer patients reported the poorest QOL and were frequently selected as the initial target population for QOL study in clinical trials due to the high incidence and the relatively rapid progression of the disease, facilitating both patient accrual and evaluation of responsiveness of the questionnaire to change in health status over time (9-12). Theoretically, the relative benefit and impact of treatment for NSCLC should be central in the evaluation of the treatment, and overall survival and response were traditionally used as the end points of the clinical trials. However, these factors are inadequate in the evaluation of treatment policy of advanced NSCLC with only modest survival benefit, even, which may be substantially improved with new agents. There is a strong need for QOL as an end point of treatment in advanced NSCLC in order that doctors and their patients can effectively discuss the trade-off of treatment (5-7), yet many clinicians seem reluctant to turn the emphasis away from the traditional end points of response and survival to QOL. We believe that in cancer therapy, equal emphasis should be given to the patient's QOL as well as to objective measurement of response.

A meta-analysis of all randomized trials comparing chemotherapy to supportive care (including palliative radiation therapy) alone in patients with advanced NSCLC was completed in 1994. This translated into an absolute improvement of median survival of two months and a 10% increase in one-year survival (14). Given these modest therapeutic benefits, no chemotherapy program can be recommended as the standard treatment for NSCLC. MIP combination is one of the most frequently used in the palliative setting of NSCLC with a response rate between 30 and 40% (13,15). There have been reports of chemotherapy leading to significant palliation and improvement of overall QOL including patients failing to achieve an objective response. The relatively high incidence of symptomatic relief (75%) was seen in MVP (mitomycin, vinblastine and moderate-dose cisplatin) chemotherapy compared to the modest objective response rate of 21% (13,16). A recent ECOG trial suggested that QOL change data were the most significant prognostic factor of survival in patients with NSCLC (8).

Well-defined and constructed QOL instruments are available to measure QOL, and these are proved to have practicality, validity and reliability in clinical trials (5-7). However, there are a few discrepancies and difficult problems between theory and practice. When assessing palliation, symptoms can be quantified by QOL measures and analyzed statistically, but there is no agreement regarding the definition of palliation and the clinical correlating factors for changes in QOL scores are unknown. Interpretation of data by statistical analysis is proving difficult and complex in practice. Often, patients and/or protocol compliance and missing data can affect the quality of QOL. Usually, compliance diminishes with the successive courses of therapy due to worsening of PS, progressive disease or death (17). We used the baseline and six-week QOL data because patients and/or protocol compliance diminished after two cycles of chemotherapy due to patient death or worsening of PS, failure to attend clinic, or administrative failure.

In this study, our central concern of QOL was symptomatic palliation including lung cancer-specific and general symptoms. In a small clinical trial, like ours, disease-specific or general symptoms have been used as QOL assessment (17). The attending physician completed the QOL-questionnaire in this study. What we needed was a readily comprehensive, convenient and reliable way for patients to make their own assessment as to their QOL before and after treatment. Priestman and Baum (19) used L.A.S.A. scales to measure 10 arbitrarily chosen aspects of the QOL of patients with cancer. They found that the change in L.A.S.A. scales correlated well with the objective response to treatment. The reliability of the assessment technique proved the high correlation between the scores for patients alone and with a doctor present (18,19).

The feature of this study was a high incidence of improved QOL (58.3%) despite a modest and short-lived response (38.9%, median 3.5 months). QOL improvement was possible without serious morbidity. Finally, a change of QOL was significant in predicting survival and integral QOL studies in a clinical trial would be expected to provide the enhanced clinical outcome.

The incidence of lung cancer is increasing and the arrival of new drugs will bring a potential for improvement in treatment. However, most patients are diagnosed at an advanced stage, and it is essential to integrate the logically implement QOL research and data recording in treatment policy for improving patient care.

Acknowledgment

We thank Dr Nagahiro Saijo (National Cancer Center Hospital at Tokyo) for his recommendation.

References

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2. Stewart LA, Pignon JP, Parmar MKB, Le Chevalier T, Souhami RL. A meta-analysis using individual patient data from randomized clinical trials of chemotherapy in non-small cell lung cancer: Survival in the supportive care setting. Proc Am Soc Clin Oncol 1994;13:337.

3. Rapp E, Pater JL, Willan A, Cormier Y, Murray N, Evans WK, 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;6:633-41. MEDLINE Abstract

4. Cartei G, Cartei F, Cantone A, Causarano D, Genco G, Tobaldin 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. MEDLINE Abstract

5. Cella DF, Tulsky DS, Gray G, Sarafian B, Linn E, Bonomi A, et al. The functional assessment of cancer therapy scale: Development and validation of the general measure. J Clin Oncol 1993;11:570-9. MEDLINE Abstract

6. Schipper H, Clinch J, McMurray A, Levitt M. Measuring the quality of life of cancer patients: The functional living index-cancer: Development and validation. J Clin Oncol 1984;2:472-83. MEDLINE Abstract

7. Coates A, Gebski V, Signorini D, Murray P, McNeil D, Byrne M, et al. Prognostic value of quality-of-life scores during chemotherapy for advanced breast cancer. J Clin Oncol 1992;10:1833-8. MEDLINE Abstract

8. Cella D, Fairclough DL, Bonomi PB, Kim K, Johnson D. Quality of life (QOL) in advanced non-small cell lung cancer (NSCLC): results from Eastern Cooperative Oncology Group (ECOG) study E5592. Proc Am Soc Clin Oncol 1997;16:2a.

9. de Haes JCJM, van Knippenberg FCE, Neijt JP. Measuring psychologic and physical distress in cancer patients: structure and application of Rotterdam symptom checklist. Br J Cancer 1990;62:1034-8.

10. Spiegel D, Bloom JR, Kraemer HC, Gottheil E. Effect of psychosocial treatment on survival of patients with metastatic breast cancer. Lancet 1989;14:888-91.

11. Aaronson NK, Ahmedzai S, Bergman B. The european organization for research and treatment of cancer QLQ-C30: A quality-of-life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 1993;85:365-76. MEDLINE Abstract

12. Bergman B, Aaronson NK, Ahmedzai S, Kaasa S, Sullivan M. The EORTC QOQ-LC13: a modular supplement to the EORTC core quality of life questionnaire (QLQ-C30) for use in lung cancer clinical trials. Eur J Cancer 1994;30A:635-42. MEDLINE Abstract

13. Cullen MH, Joshi R, Chetiyawardana AD, Woodroffe CM. Mitomycin, ifosfamide and cisplatin in non-small cell lung cancer: Treatment good enough to compare. Br J Cancer 1988;58:359-61. MEDLINE Abstract

14. Sause W, Scott C, Taylor S, Johnson D, Livingston R, Komaki R, et al. RTOG 8808 ECOG 4588, preliminary analysis of phase III trial in regionally advanced unresectable non-small cell lung cancer. Proc Am Soc Clin Oncol 1994;13:325.

15. Cullen MH. Trials with mitomycin, ifosfamide and cisplatin in non-small cell lung cancer. Lung Cancer 1995;12(suppl. 1):S95-106. MEDLINE Abstract

16. Hardy JR, Noble T, Smith IE. Symptomatic relief with moderate dose chemotherapy (mitomycin-C, vinblastine and cisplatin) in advanced non-small cell lung cancer. Br J Cancer 1989;60:764-6. MEDLINE Abstract

17. Hopwood P. Quality of life assessment in chemotherapy trials for non-small cell lung cancer: Are theory and practice significantly different? Semin Oncol 1996;23:60-4. MEDLINE Abstract

18. Coates A, Dillenbeck CF, McNeil DR, Kaye SB, Sims K, Fox RM, et al. On the receiving end-II. Linear analogue self-assessment (LASA) in evaluation of aspects of the quality of life of cancer patients receiving therapy. Eur J Cancer Clin Oncol 1983;19:1633-7. MEDLINE Abstract

19. Priestman TJ, Baum M. Evaluation of quality of life in patients receiving treatment for advanced breast cancer. Lancet 1976;1:899-900. MEDLINE Abstract

Received July 27, 1998; accepted September 29, 1998
For reprints and all correspondence: Ji-Youn Han, Department of Internal Medicine, St Paul's Hospital, College of Medicine, the Catholic University of Korea, 620-56 Jeonnong-Dong, Dongdaemun-Gu Seoul 130-022, Korea. E-mail: jymama{at}hotmail.com
Abbreviations: QOL, quality of life; NSCLC, non-small cell lung cancer; ECOG, Eastern Cooperative Oncology Group; CT, computed tomography; MIP, mitomycin, ifosfamide cisplatin; L.A.S.A., linear analog self-assessment; CI, confidence interval; SE, standard error; PS, performance status; MVP, mitomycin, vinblastine, cisplatin; PR, partial response; NC, no change; PD, progressive disease

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Copyright©Japanese Journal of Clinical Oncology, 1998.
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