Journal of Clinical Oncology, Vol 17, Issue 10
(October), 1999: 3188-3194
© 1999 American Society for Clinical Oncology
Mitomycin, Ifosfamide, and Cisplatin in Unresectable Non–Small-Cell Lung Cancer: Effects on Survival and Quality of Life
M. H. Cullen,
L. J. Billingham,
C. M. Woodroffe,
A. D. Chetiyawardana,
N. H. Gower,
R. Joshi,
D. R. Ferry,
R. M. Rudd,
S. G. Spiro,
J. E. Cook,
C. Trask,
E. Bessell,
C. K. Connolly,
J. Tobias,
R. L. Souhami
From the Queen Elizabeth Centre for the Treatment of Cancer, University Hospital Birmingham, Birmingham; Cancer Research Campaign Institute for Cancer Studies, University of Birmingham, Birmingham; University College Hospitals Trust, London; Royal Hospitals Trust, London; Walsall Manor Hospital Trust, Walsall; Southend Hospital Trust, Southend; Nottingham City Trust, Nottingham; and Darlington Hospital Trust, Darlington, United Kingdom.
Address reprint requests to M.H. Cullen, MD, Queen Elizabeth Centre for the Treatment of Cancer, University Hospital Birmingham, B15 2TH, United Kingdom; email michael.cullen{at}university-b.wmids.nhs.uk
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ABSTRACT
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PURPOSE: Chemotherapy for non–small-cell lung cancer (NSCLC) remains controversial. We describe the two largest reported, randomized, parallel trials designed to determine whether the addition of chemotherapy influences duration and quality of life in localized, unresectable (mitomycin, ifosfamide, cisplatin [MIC]1 trial) and extensive (MIC2 trial) disease.
PATIENTS AND METHODS: Ambulatory patients with NSCLC, aged 75 years or younger, with localized disease, were randomized in MIC1 to receive up to four cycles of chemotherapy (CT: mitomycin 6 mg/m2, ifosfamide 3 g/m2, and cisplatin 50 mg/m2) every 21 days, followed by radical radiotherapy (CT + RT) or radiotherapy (RT) alone. Extensive-stage patients were randomized in MIC2 to identical chemotherapy plus palliative care (CT + PC) or palliative care (PC) alone. Short-term change in quality of life (QOL) was assessed in a subgroup of patients. Data from the two trials were combined to allow multivariate and stratified survival analyses.
RESULTS: Seven hundred ninety-seven eligible patients were randomized, 446 in MIC1 and 351 in MIC2. MIC CT improved survival in both trials (significantly in MIC2). The median survival time in MIC1 was 11.7 months (CT + RT) versus 9.7 months (RT alone) (P = .14); whereas in MIC2, median survival time was 6.7 months (CT + PC) compared with 4.8 months (PC alone) (P = .03). QOL, assessed in 134 patients from start of trial to week 6, showed improvement with chemotherapy and deterioration with standard treatment. In the combined analysis of 797 randomized patients, the positive effect of MIC on survival was significant overall (P = .01) and after adjusting for prognostic factors (P = .01).
CONCLUSION: MIC chemotherapy prolongs survival in unresectable NSCLC without compromising QOL.
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INTRODUCTION
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DESPITE SOME EVIDENCE supporting a role for chemotherapy (CT) in inoperable non–small-cell lung cancer (NSCLC), routine management practice varies widely across the developed world. In the United States, for example, the use of CT is standard for good-performance-status patients with stage III or IV disease, whereas in the United Kingdom and much of mainland Europe, CT is still not routinely offered, even in stage III disease. Instead, radical radiotherapy (RT) alone is used for the minority of patients with localized disease, and palliative care (PC) alone is used for those with more advanced or metastatic disease. Some trials evaluating CT have shown no survival benefit.1,2 However, others, particularly trials including cisplatin, have demonstrated an advantage.3,4 These trials have been small and, hence, lacked the power to effect a widespread change in management practice across the developed world.5 Furthermore, the side effects of treatment have been regarded by many as outweighing the benefit of a modest extension of life.6 In 1995, a meta-analysis of trials concluded that cisplatin-based CT does confer a small survival benefit.7 However, meta-analyses have been criticized on a number of counts8; they give no clear guidance on choice of regimen, toxicity, and quality-of-life (QOL) outcomes and are no substitute for large, randomized trials.
In 1988, we reported a phase II study of mitomycin, ifosfamide, and cisplatin (MIC) in NSCLC, with a high objective response rate, good side-effect profile, and improvement in performance status (PS) in responding patients.9 In two parallel phase III trials (MIC1 and MIC2), we have compared for our study, MIC chemotherapy plus standard treatment (ST) with ST alone in 820 randomized patients with unresectable NSCLC to examine the effects primarily on survival but also, in a subgroup of trial patients, QOL. In the United Kingdom, ST consists of RT for patients with localized unresectable disease (MIC1 trial) and PC for patients with extensive disease (MIC2 trial). The trials had identical design, were conducted at the same time by the same collaborative groups, and, apart from stage of disease, had identical eligibility criteria. As well as reporting the trials separately, the data were combined to enable the overall effect of CT in unresectable NSCLC to be assessed in comparison with nonchemotherapeutic treatment.
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PATIENTS AND METHODS
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Eligibility
Trial patients were required to have previously untreated, unresectable, histologically or cytologically proven NSCLC (squamous, adeno-, or large-cell carcinoma) that could be measured or assessed. Patients were 75 years of age or less, with World Health Organization performance scores of 0, 1, or 2. Patients with symptomatic superior vena caval obstruction, cerebral metastases, previous malignancy, spinal cord compression, or impaired renal function (glomerular filtration rate < 70 mL/min or serum creatinine > 115 mmol/L) were excluded. Patients with no clinical evidence of metastatic disease (except ipsilateral supraclavicular lymphadenopathy) and no pleural effusion and tumors encompassable in a radical RT volume were eligible for the MIC1 trial; the remainder were eligible for the MIC2 trial. Staging was essentially clinical, based on history, physical examination, chest radiograph, blood chemistry profile, and full blood count. More detailed staging investigations were performed when indicated. For instance, patients with symptoms suggesting skeletal metastases had bone scans, and those with biochemical evidence of liver secondary tumors had computed tomography or ultrasound scans.
Treatment
CT (MIC1 and MIC2 trials).
The treatment regimen is listed in Table 1. In the early years of the trial, antiemetic therapy consisted of high-dose metoclopramide via intravenous infusion with intravenous dexamethasone. After the introduction of 5-hydroxytryptamine-3 antagonists, the metoclopramide was replaced by a single intravenous dose of granisetron 3 mg or ondansetron 8 mg.
CT treatment cycles were repeated every 21 days, with a maximum of four cycles. CT was discontinued if there was progressive disease at any stage, static disease after two cycles, unrelieved local symptoms, or unacceptable toxicity. During the period of these trials, CT was rarely used in advanced NSCLC in the United Kingdom. Hence, it was regarded as quite ethical and scientifically desirable not to allow its use at any stage in the control arms, and second-line or nonprotocol CT was not permitted.
RT (MIC1 trial).
Dose and fractionation schedules for RT in limited NSCLC vary in different United Kingdom centers. To encourage maximum participation, a single dose/fractionation scheme was not specified, but patients were required to receive a total dose equivalent to not less than 40 Gy in 15 fractions. In the control arm, RT was commenced after randomization and planning. In the CT arm, RT was commenced 3 weeks after completion of four courses of MIC but could be given early if CT failed. Patients who developed distant metastatic disease were withdrawn from further protocol treatment but continued on trial follow-up, receiving palliative therapy, including, where appropriate, RT.
Palliative care, (MIC2 trial).
PC, including RT, antibiotics, cough suppressants, analgesics, and so on, was given to all patients without restriction according to the standard practice of the collaborating centers. After treatment, all patients were seen for routine review with chest radiograph at 2-month intervals until the end of the first year after diagnosis and 3-month intervals, thereafter.
Response Criteria
Objective response assessment was based on physical examination and chest radiograph. Routine rescanning was not required because response rate was not a primary outcome. It is possible that response defined in this way may give a higher value than when the definition requires rescanning, as in phase II studies. The decision to continue with a second and subsequent cycles of MIC was further supported by subjective assessment of symptomatic improvement and toxicity.
Final response to CT was assessed on completion of all CT treatment, however many courses patients had received. Assessable and measurable lesions were considered for treatment response.10 Response was defined as follows: complete response, complete clinical and radiologic disappearance of measurable or assessable lesions; partial response, greater than 50% reduction in size of measurable lesions or regression of assessable lesions.
Trial Design
Both trials were multicenter, prospective, randomized studies. The Birmingham and London Lung Cancer Groups collaborated in the MIC1 trial. The MIC2 trial involved only the Birmingham Group. The designs of the two trials were deliberately identical and ran concurrently to enable a prospective pooling of the data. Randomization was by telephone call to one of the two randomization centers, the CRC Trials Unit (Birmingham, United Kingdom) or the Clinical Trials Office of the London Lung Cancer Group. In MIC1, randomization was stratified by radiotherapist to ensure that variation in clinical practice was distributed evenly between the two arms. The primary end point for the studies was survival, with toxicity, response to treatment, and QOL as secondary end points. Patient sample sizes of 500 (MIC1) and 300 (MIC2) were planned on the basis of detecting an improvement from 5% to 10% in the 5-year survival rate for MIC1 and from 10% to 20% in the 1-year survival rate for MIC2, with 80% power and 5% significance level.
QOL Study Design
QOL data were collected in an unselected subgroup of trial patients. These were from three centers where a QOL research nurse was available to minimize noncompliance and maximize completeness of data. The QOL research nurses were based in clinics where CT was administered, which facilitated access to patients in the CT arms. Consequently, there were more CT patients in the QOL study than controls. The questionnaire, based on the lung cancer module of the European Organization for Research and Treatment of Cancer (EORTC) QOL questionnaire (EORTC QLQ-LC13),11 had 12 questions assessing symptoms and toxicity, cough, breathlessness (at three different exercise levels), hemoptysis, pain, appetite, anxiety, depression, dysphagia, nausea, and malaise. Responses were given on a category-rated scale, as none, a little, quite a bit, and very much, and were scored 0, 1, 2, and 3, respectively. Patients completed questionnaires at approximately 3-week intervals from the first pretreatment questionnaire to a maximum of five on the CT arm and four on ST. A minimum of 3 weeks was allowed after radical RT in MIC1 for the 6-week assessment.
Statistics
Methodology for trial data.
Response rates were compared using a  2 test and were calculated for assessable patients and those unassessable because of disease or treatment-related factors (ie, died before CT started). Survival was measured from the date of randomization to either the date of death (all causes), censor date for the analysis (January 1, 1997), or, if not observed up to that time, date last seen alive. The Kaplan-Meier12 method was used to estimate survival curves, and differences between treatments were assessed using the log-rank test. In the survival analysis of the combined data, treatment comparisons were adjusted for the separate effects (stratified log-rank tests) and combined effects (Cox proportional hazards regression) of various patient characteristics, ie, sex, age, PS, histologic diagnosis, and trial (representing stage of disease).13
Methodology for QOL study.
A mean QOL score was calculated for each individual from responses to the questionnaire. The first and third questionnaires were used to calculate the 0- to 6-week change in QOL score. Treatment groups were compared using t tests together with multiple regression analysis to adjust for imbalances in distribution of sex, PS, age, and histologic diagnosis.
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RESULTS
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Patient Characteristics
Between March 1988 and March 1996, 820 patients were randomized, 461 in MIC1 and 359 in MIC2. Fifteen patients in MIC1 and eight in MIC2 were ineligible. These patients were excluded, and sensitivity analysis confirmed that the conclusions were unaffected. MIC1 protocol violations included two RT patients given CT, seven patients who received nonprotocol RT (all nine excluded from response to RT), and 10, mainly RT patients, who had CT on relapse (included in all analyses). In MIC2, two patients had CT on progression (included in all analyses). The treatment groups in both trials were well balanced with respect to patient characteristics (Table 2).
CT Treatment Details and Response
Sixty-two percent of eligible patients (138 of 222; one protocol violation) in MIC1 and 50% of eligible patients (88 of 175) in MIC2 had four courses of MIC. CT was discontinued early in 35 patients in MIC1 and in 34 in MIC2 as a result of nonresponse. Toxicity contributed to early cessation of CT in 28 and 24 patients in MIC1 and MIC2, respectively. In addition, four patients in MIC1 and three in MIC2 requested early discontinuation of CT. No treatment-related deaths occurred in MIC2, but there were three CT-related deaths (all with neutropenic sepsis, one complicated by renal failure) and three deaths from the combined effects of CT + RT in MIC1 (pneumonitis in three patients, complicated by infection in one).
Of the potentially delayable (ie, second, third, and fourth) CT cycles, only 13% (65 of 491) and 9% (27 of 315) in MIC1 and MIC2, respectively, were postponed by more than 2 days. Delays were mainly because of hematologic toxicity or infection. Early cessation and treatment delays (as indicators of tolerance to CT) were observed no more frequently in patients with a PS of 2 than in patients with better PS scores.
Objective response to CT was assessed in 88% of patients in MIC1 and 89% in MIC2. The remainder of patients either had missing or inassessable x-rays, refused CT, violated protocol, or died from nondisease/nontreatment-related cause before assessment. Of the assessable patients, the objective response rates (complete response plus partial response) were 54% (105 of 196; 95% confidence interval [CI], 47% to 61%) in MIC1 and 32% (49 of 155; 95% CI, 24% to 39%) in MIC2, with 10% and 2% complete responses in each trial, respectively.
RT Treatment Details and Response
In the MIC1 trial, 68% of patients (152 of 223) on the CT + RT arm received their planned radical dose of RT compared with 85% (189 of 223) on the RT arm. Patients did not receive radical RT because they were too sick, developed progressive disease, or died. Although the proportions of patients having radical RT were different on the two arms, the received doses and schedules were very similar (Table 3).
Eighty-three percent of CT + RT patients and 81% of RT patients in MIC1 were assessable for response after all treatment. The objective response rate to CT + RT was 53% (98 of 185; 95% CI, 46% to 60%) on the combined-modality arm and 45% (83 of 185; 95% CI, 38% to 52%) on the RT alone arm (2 = 2.43, P = .12), with 20% and 9% complete responses in each arm, respectively.
In the MIC2 trial, 40% (70 of 175) of patients on the CT + PC arm compared with 68% (120 of 176) on the PC arm received RT, which was thoracic in 51 and 99 patients, respectively. The median thoracic RT dose of 30 Gy and interquartile range of 20 Gy to 35 Gy were identical for the two arms of the trial.
Survival
On January 1, 1997, eight patients were lost to follow-up. Of the remainder, 33 patients in MIC1 were still alive (median follow-up, 31 months; range, 12 to 102 months) and six in MIC2 remained alive (median follow-up, 26 months; range, 17 to 45 months).
In both trials, survival was longer on the CT arm compared with ST (Fig 1; Table 4). The median survival in MIC1 was 11.7 months (95% CI, 9.5 to 14.0) on the CT + RT arm compared with 9.7 months (95% CI, 8.0 to 11.4) on RT alone, while in MIC2 median survival was 6.7 (95% CI, 5.4 to 8.0) months (CT + PC) compared with 4.8 months (95% CI, 4.0 to 5.7) on PC alone. In MIC1, the differences in survival did not reach conventional levels of statistical significance (2 = 2.20, P = .14), but they were statistically significant in MIC2 (2 = 4.87, P = .03).
Combined Analysis of Survival
The two concurrently run trials, in a stage continuum of 797 patients with inoperable NSCLC, had identical designs that involved randomization between ST alone versus MIC plus ST. Furthermore, because the observed treatment effect is very similar in the two trials, combining the data is valid. When combined, survival was statistically superior on the CT arm compared with ST (2 = 6.66, P = .01). Trial (ie, stage: localized or extensive), PS, and histology were significant prognostic factors for survival; sex and age were not (Table 5). Cox regression analysis showed that trial, PS, and histology were independent prognostic factors for survival, and after adjusting for these, the effect of MIC was still significant (P = .01), with a 21% (95% CI, 4% to 41%) increased hazard of death on ST (Table 6).
QOL
The QOL subgroup comprised 67 patients from MIC1 (42 from CT + RT arm and 25 from RT arm) and 109 patients from MIC2 (67 from CT + PC arm and 42 from PC arm). The number of patients in the MIC1 and MIC2 trials responding to the third questionnaire at 6 weeks from baseline was reduced to 50 and 84, respectively, with similar dropout rates on both arms of the trials (29% compared to 20% for CT + RT and RT arms, respectively, in MIC1, and 22% compared to 24% for CT + PC and PC arms, respectively, in MIC2). In MIC1, the mean 0- to 6-week change in QOL score was -0.22 (95% CI, -0.36 to -0.08) on the CT arm compared with 0.28 (95% CI, 0.03 to 0.53) on ST, whereas in MIC2 the corresponding QOL figures were -0.09 for CT (95% CI, -0.21 to 0.03) and 0.20 for ST (95% CI, 0.01 to 0.4). Negative values imply that the level of symptom scores reduced, on average, over the 0- to 6-week time period, thus indicating an improvement in QOL. Positive values indicate deterioration. The results for both trials show that, during the 6 weeks from starting treatment, QOL improved on CT (significantly in MIC1) but deteriorated on ST (significantly in both trials). The difference between treatment arms was statistically significant (P = .0002 for MIC1 and P = .007 for MIC2) and, after adjusting for imbalances in patient characteristics between the treatment groups, remained highly significant for MIC1 and became borderline significant for MIC2 (P = .0003 for MIC1 and P = .06 for MIC2).
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DISCUSSION
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Real interest in CT for NSCLC began in the early 1980s with the demonstration that several cisplatin-based regimens could induce objective responses in up to 50% of cases.14 The next step was to quantify the clinical value, if any, of such intervention. Attempts so far have focused largely on duration of life in randomized trials, which frequently have been too small to detect the modest improvements likely with current regimens. In our two large trials, MIC has been simultaneously evaluated in terms of both quantity and quality of life. Mitomycin, ifosfamide, and cisplatin are three of the most active single agents in NSCLC, and phase II data for the MIC combination were first reported in the late 1980s.9,15 Since then, MIC has been tested and its activity confirmed in various contexts in randomized trials in stage IIIA,16 IIIB, and IV disease.17 The objective response rates of 54% in localized, unresectable disease and 32% in extensive disease imply that MIC is among the most effective regimens in NSCLC and is at least as active as more recently described combinations like paclitaxel/carboplatin,18 gemcitabine/cisplatin,19 and vinorelbine/cisplatin.20 The objective response rate in the control arm of the MIC1 trial is similar to that reported by others for radical RT in localized, inoperable NSCLC.21,22
In localized disease (MIC1), we found no statistically significant survival advantage with the addition of MIC, although there was a trend in favor of CT. This result is almost identical to that reported by Le Chevalier et al23 in the only other trial of similar design with more than 300 cases. Survival at 1 year was 41% for RT alone in both trials compared with 50% and 49% in the French and MIC trials, respectively, in the CT + RT arms. At 2 years, the corresponding figures for RT alone were 14% (French trial) and 16% (MIC) compared with 21% and 20%, respectively, for CT + RT in the two trials. A later analysis of the French trial reported a statistically significant benefit for CT + RT versus RT alone.24 Preliminary results from an intergroup trial in the United States, which included only good-risk patients, also show a benefit from the addition of cisplatin-based chemotherapy.25
In advanced disease (MIC2), the picture is clearer, with a significant prolongation of life in the CT arm. Other smaller trials with cisplatin-based CT have come to a similar conclusion,4,26 but there has not been widespread adoption of CT for the management of stage IV NSCLC. Raby et al6 reported that, although a majority of Canadian clinicians involved in lung cancer therapy believed CT prolonged median survival in stage IV NSCLC, only 20% would recommend it for an asymptomatic patient. The authors believed that, although randomized trials may demonstrate that a treatment works, they often fail to show that it is worthwhile.
Toxicity is frequently cited as a reason to withhold CT. The QOL component of the present trials was incorporated to quantify symptom relief and toxicity formally. A short-term assessment was chosen to minimize the effect of subject dropout, which complicates QOL analyses in situations where patients deteriorate rapidly and allows evaluation of rapid symptom relief, which is vital in patients with short life expectancy. Drop out rates were similar in both arms of each trial, validating treatment comparisons. These comparisons showed an improvement in QOL in patients undergoing CT, implying palliation outweighed short-term toxicity as well as a deterioration in patients on ST. A more detailed analysis examining other time points, with similar overall conclusions, will be reported separately.
Others have reported symptom improvement resulting from CT treatment in NSCLC, even in the absence of objective tumor response.27 In an interesting, recent American study, NSCLC patients who had experienced cisplatin-based CT were asked to indicate the minimum survival benefit required to accept the side effects of CT for advanced disease. For a realistic survival benefit of 3 months, only 22% chose CT against supportive care. However, 68% chose CT if it substantially reduced symptoms without prolonging life.28
The identical basic design and similar treatment effects of these trials permitted amalgamation of the survival data, allowing a comparison of MIC with ST in almost 800 randomized patients with unresectable NSCLC. In common with other trials, we found PS, stage, and histologic diagnosis to be independent prognostic factors for survival,29 and, having adjusted for the effects of these, the positive impact of MIC on survival remained significant. An examination of CT effect across strata defined by a number of pretreatment patient characteristics is being prepared for separate publication.
There is now a considerable body of evidence that supports a small beneficial effect of cisplatin-based CT on survival in advanced NSCLC. The results presented here, from the two largest reported trials of one of the most active regimens,30 are fully consistent with the meta-analysis of smaller trials.7 The effect of MIC on survival, seen in each trial separately, is reinforced by the consistently significant treatment effect observed in the combined data. We have also shown that the treatment effect is not achieved at the expense of short-term QOL. Thus, MIC is an important comparator candidate for future trials aiming to identify regimens with greater impact on duration of life, without compromising quality.
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APPENDIX
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This work resulted from a collaboration between the Birmingham and London Lung Cancer Study Groups. The principle contributors other than the listed authors were: C. Skinner, J. Ayres, D. Stableforth, F. Collins, S. Burge (from Heartlands Hospital Trust, Birmingham, United Kingdom); A. Goodman, G. Blackledge, N. James, D. Spooner, H. Earl (from Queen Elizabeth Centre for the Treatment of Cancer, University Hospital Trust, Birmingham, United Kingdom); B. Mantell, N.C. Barnes, N. Plowman (Royal Hospitals Trust, London, United Kingdom); W. Pratt, P. Murray (Essex County Hospital Trust, Colchester, United Kingdom); A.C. Robinson, A. Lamont, C.D. Eraut (Southend Hospital Trust, Southend); F. Macbeth (Beatson Oncology Centre, Glasgow, United Kingdom); C. Macmillan (Northampton General Hospital Trust, Northampton); M. Henk (Royal Marsden Hospital Trust, London, United Kingdom).
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ACKNOWLEDGMENTS
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Supported by grants from the Cancer Research Campaign, Asta Medica AG (Frankfurt am Main), Kyowa Hakko United Kingdom Ltd, and the Oliver Prenn Foundation
We thank Janet Dunn, Janet Woods, Angela Murphy, Lindsay James, Ruth Allen, Jane Drake, Lillian Daniels, Helen Bartram, and Sue Alcock.
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Submitted September 14, 1998;
accepted June 2, 1999.
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TOP
ABSTRACT
INTRODUCTION
