Affiliations of authors: N. van Zandwijk, O. Dalesio, H. van Tinteren, The Netherlands Cancer Institute, Amsterdam; U. Pastorino, European Institute of Oncology, Milan, Italy; N. de Vries, St. Lucas Hospital, Amsterdam.
Correspondence to: Nico van Zandwijk, M.D., Ph.D., The Netherlands Cancer Institute, Plesmanlaan 121, 1066 CX Amsterdam, The Netherlands (e-mail: zandwijk{at}nki.nl).
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ABSTRACT |
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INTRODUCTION |
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Tobacco smoke is also a source of oxidative free radicals that can damage DNA (8). Antioxidants have been shown to prevent cellular damage and the subsequent development of cancer by neutralizing free radicals (9,10). Interest has arisen, in particular, in N-acetylcysteine, an aminothiol and synthetic precursor of intracellular cysteine and glutathione, which has been widely used in the past as a mucolytic agent and antidote against paracetamol (acetaminophen)-induced hepatotoxicity. N-Acetylcysteine has proven to be effective in decreasing the direct mutagenicity of several chemical compounds by inhibiting the in vivo formation of carcinogenDNA adducts, DNA damage, and urethane-induced lung tumors in mice (1113).
The EUROSCAN Study (i.e., the European Study on Chemoprevention With Vitamin A and N-Acetylcysteine) was designed to test whether vitamin A (retinyl palmitate) and N-acetylcysteine could improve the prognosis of patients treated for head and neck cancer or for lung cancer by preventing second primary tumors (14). Both categories of patients have a high risk of developing a second cancer and represent a relevant population for secondary preventive measures (15). Two earlier, albeit relatively small, studies of 13-cis-retinoic acid and retinyl palmitate in the same groups of patients (16,17) suggested that these agents had protective activity, but large randomized chemoprevention trials with vitamin A and ß-carotene in smokers (18,19) failed to show any preventive effect.
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PATIENTS AND METHODS |
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The two agents studied have different mechanisms of action, and the combination was judged to be feasible without dose reductions or delays. A two-by-two factorial design was chosen to allow the simultaneous investigation of retinyl palmitate and N-acetylcysteine. Initially, the EUROSCAN Study also included a pilot study on the effectiveness of six monthly bronchoscopies as a screening tool for patients with laryngeal cancer. This part of the study was closed because only a minority of patients agreed to participate (20).
Participants were randomly assigned to one of the following four arms: 1) retinyl palmitate alone (300000 IU daily for 1 year followed by 150000 IU for the 2nd year), 2) N-acetylcysteine alone (600 mg daily for 2 years), 3) the combination of retinyl palmitate (300000 IU daily for 1 year followed by 150000 IU for the 2nd year) and N-acetylcysteine (600 mg daily for 2 years), or 4) no intervention (Fig. 1). The possibility of a placebo-controlled study was discarded after considering the cost aspects and the distinct characteristics (smell and side effects) of the two agents in the double-blind approach.
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Patient Eligibility
To be eligible for the study, patients had to have non-small-cell lung cancer (stages pT12, N01, and T3N0, according to the 1987 edition of the tumornodemetastasis [TNM] staging system, published by the Union Internationale Contre le Cancer (22), cancer of the larynx (Tis, T13, and N01), or cancer of the oral cavity (T12 and N01); had to have a performance status (World Health Organization [WHO]) 02; and had to be treated with curative intent. Patients with recurrent disease, synchronous multiple tumors, previous malignant disease, abnormal liver or renal function, hypertriglyceridemia, hypercholesterolemia, diabetes mellitus, hypertension, and recent or active peptic ulcer were considered to be unsuitable for the study. Informed consent from all patients was to be obtained according to institutional regulations. From June 1988 through July 1994, a total of 2592 patients (60% with head and neck cancer and 40% with lung cancer) from 81 institutions in 15 countries were randomly assigned.
Evaluation of End Points
Minimal follow-up requirements during the first 2 years after randomization consisted of three monthly follow-up visits, with chest x-rays every 6 months. For patients with laryngeal cancer, ear, nose, and throat examinations included repeated laryngoscopies. For patients with oral cancer, follow-up investigations included inspection of the oral cavity; no routine laryngoscopy was performed in this category of patients. From years 3 through 10 after randomization, follow-up was scheduled at 6-month intervals and chest x-rays were scheduled yearly. At every follow-up visit, patients were asked about pill intake, side effects, concomitant medications, and smoking habits. Patients taking retinyl palmitate were regularly checked for levels of serum enzymes, cholesterol, and triglycerides.
Primary end points were event-free survival, overall survival, and the occurrence of a second primary tumor. Carcinomas of the head and neck, lung, esophagus, and urinary bladder were considered to be tobacco-related second primary tumors. The study coordinators reviewed all first events. When inconsistencies or doubts arose, additional information was requested from the responsible physician, and the study coordinators discussed the case until a consensus was reached.
Statistical Considerations
The sample size was chosen to provide 90% power to detect a decrease from 10% to 5% in the rate of (tobacco-related) second primary tumors at 5 years (significance level = .05; two-sided log-rank test). The number was increased to take into account a possible dilution effect caused by 10% crossing-over (e.g., 10% of the patients randomly assigned to retinyl palmitate not taking their pills and 10% of the patients assigned to the no retinyl palmitate arms taking retinyl palmitate). With continuous follow-up, sufficient number of events (recurrences, second primary tumors, and deaths) would be observed to allow the detection of a 20% reduction in the hazard ratios with 80% power (significance level = .05; two-sided log-rank test). Therefore, at least 2000 patients were to be entered and followed for at least 5 years (500 patients per arm).
In the factorial design, the effect of N-acetylcysteine could be evaluated by comparing patients randomly assigned to receive N-acetylcysteine (half with retinyl palmitate and half without retinyl palmitate) with patients randomly assigned not to receive N-acetylcysteine (half with retinyl palmitate and half without retinyl palmitate). This comparison was done by stratifying by the presence or absence of retinyl palmitate. In a similar way, the effect of retinyl palmitate was evaluated by stratifying by the presence or absence of N-acetylcysteine.
Event-free survival, time to second primary tumor, and survival curves were constructed by the KaplanMeier technique (23) and were compared by the log-rank test (24). The interaction between the effects of N-acetylcysteine and those of retinyl palmitate was tested with a proportional hazards model. Also, analyses of four arms were performed. All analyses were intention-to-treat analyses. All statistical tests were two-sided, and P values of results referred to as statistically significant were less than .05.
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RESULTS |
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Of the 2592 patients who were randomly assigned, 19 (0.7%) were excluded from all tables and analyses because no information was received after registration as depicted in the CONSORT diagram (Fig. 1). Of the remaining 2573 patients, 1290 were assigned to retinyl palmitate arms (647 to retinyl palmitate alone and 643 to retinyl palmitate and N-acetylcysteine) and 1283 were assigned to no retinyl palmitate arms (641 to no treatment and 642 to N-acetylcysteine alone). The same patients can also be grouped with respect to treatment with N-acetylcysteine as follows: 1285 patients were assigned to N-acetylcysteine arms, and 1288 patients were assigned to no N-acetylcysteine arms.
Table 1 shows the characteristics of patients as a function of treatment. Sixty percent of the patients had head and neck cancer (1065 patients had laryngeal cancer, and 485 had oral cancer), and 40% (1023 patients) had lung cancer. The majority of patients had been treated for a stage I tumor. The median age was 61 years, 13.0% were female, and 6.5% reported that they had never smoked. In the majority of patients, the primary treatment consisted of surgery alone or surgery in combination with radiotherapy. A minority (3.4%) of patients received chemotherapy in addition to local treatment. Half of the patients were enrolled in the study shortly after treatment (within 2 months), and 16.4% of the patients had been treated for longer periods before randomization (>12 months).
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In total, more than 19000 control visits were reported. Seventy-seven percent of these visits were on schedule. The mean follow-up intensity (calculated per patient as the number of days in follow-up divided by the number of follow-up visits) was 189 days in the combined arm, 179 days in the retinyl palmitate alone arm, 186 days in the N-acetylcysteine alone arm, and somewhat longer (193 days) in the no treatment arm. The total follow-up was 8923 person-years (person-years = the total observation time added over all subjects, expressed in years) and was well balanced across treatment arms (2213 years in the retinyl palmitate alone arm, 2249 years in the retinyl palmitate and N-acetylcysteine arm, 2230 years in the N-acetylcysteine alone arm, and 2232 years in the no treatment arm). The year of last follow-up was distributed similarly across treatment arms.
Of the 93.5% of the patients who enrolled in the study with a smoking history, 25% continued to smoke after the diagnosis (9.4% admitted that they continued to smoke, and 15.6% reported periods when they resumed smoking) and 72.3% had permanently stopped (no information was obtained for 2.7% of the patients). These percentages were similar in all four arms of the study.
Compliance, Side Effects, and Concomitant Medication
Of the 1932 patients randomly assigned to receive trial medication, 444 (23%) did not complete the intended 2-year intervention period. Of the 643 patients randomly assigned to receive retinyl palmitate and N-acetylcysteine, 162 (25.2%) stopped treatment; of the 647 patients randomly assigned to receive retinyl palmitate only, 167 (25.8%) stopped treatment; and of the 642 patients randomly assigned to receive N-acetylcysteine only, 115 (17.9%) stopped treatment. Stopping treatment was more frequent in the two groups assigned to retinyl palmitate (P<.001). For 250 (13%) of 1932 patients, the drug intake was recorded as being irregular at least once during the 2-year intervention.
Overall, retinyl palmitate elicited more side effects than N-acetylcysteine (P<.001). Side effects were reported by 45% of the patients in the two retinyl palmitate arms and by 24% of the patients in the N-acetylcysteine alone arm. Typical side effects of retinyl palmitate were mucocutaneous (dryness, desquamation, itching, bleeding, and hair loss). Side effects of the N-acetylcysteine arms were more frequently related to the digestive tract (mainly dyspepsia). Severe side effects were also more frequent in the retinyl palmitate arms (Table 2).
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Co-medication was recorded on the follow-up forms of 52% of the patients. From these 1338 patients, a sample of 342 (26%), balanced for treatment groups and institution, was selected. The names of the co-medications were translated into generic terms according to the Anatomical Therapeutic Chemical Classification (25), and the co-medications were labeled if they belonged to a category with chemopreventive potential (vitamins, various brands of N-acetylcysteine, and other antioxidants). Of all the medications specified, 129 of 3125 compounds were found to belong to the same category as the study drugs (antioxidants or vitamin A-like). Within the sample, 15 (4%) of 342 patients were taking these co-medications.
Event-Free Survival, Overall Survival, and Second Primary Tumors
At 5 years, 58% of the patients with lung cancer, 83% of the patients with cancer of the larynx, and 77% of the patients with oral cancer were alive (Fig. 2).
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In an attempt to consider actual drug intake, the same analyses were also performed by taking into account compliance as baseline covariates. These analyses showed consistently similar results, suggesting that lack of compliance did not play a major role in the negativity of the results.
Event-free survival, survival, and time to second primary tumor were compared by treatment (N-acetylcysteine versus no N-acetylcysteine and retinyl palmitate versus no retinyl palmitate) within subgroups. The subgroups were defined by the presence or absence of the other treatment, site of disease, prior treatment, performance status, sex, smoking habits, and interval between treatment of the primary tumor and random assignment. These analyses should be considered exploratory because they were not planned before the study was initiated.
For the groups receiving N-acetylcysteine, the hazard ratios of event-free survival, survival, and tobacco-related second primary tumor are summarized in Fig. 5, AC. For the groups receiving retinyl palmitate or no retinyl palmitate, the hazard ratios of event-free survival, survival, and tobacco-related second primary tumor are summarized in Fig. 5, DF
. The confidence intervals for all subgroups cross the no-effect line, indicating no differences beyond what could be consistent with chance for these groups. In addition, analyses by stage of disease within the three tumor sites were performed and did not suggest any particular heterogeneity of results (data not shown).
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DISCUSSION |
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The incidence of second primary tumors in the EUROSCAN Study was approximately what was described in previous series of patients (15,26), with the exception of a recent report (27) on a similar group of patients with lung cancer who had a considerably higher rate. Differentiation between second primary tumors and recurrences (especially when the new lesion occurs near the original tumor site) or between second primary tumor and solitary metastasis (in case of similar histology) is difficult and sometimes impossible (15). Ideally for a definite diagnosis, new molecular methods (28) should have been used. However, this technology was not yet available for implementation in a large multicenter trial, such as the EUROSCAN Study. Although all first events in the study were centrally reviewed, a certain degree of misclassification cannot be excluded. Therefore, emphasis was put on incontestable end points, such as overall survival and event-free survival.
Results of the EUROSCAN Study do not confirm the positive outcomes of previous studies with retinyl palmitate (17) and 13-cis-retinoic acid (16), suggesting preventive activity in patients who have had non-small-cell lung cancer or head and neck cancer treated with curative intent. These studies were small and had a shorter follow-up (32 and 46 months versus 49 months) and a shorter intervention period. Two other relatively small studies (29,30) in which patients with head and neck cancer were treated with retinoids (retinyl palmitate and etretinate) have also failed to show a decrease in the number of second primary tumors. It is, therefore, not surprising that doubt about the potential of vitamin A to prevent cancer has increased (31).
Other large-scale prevention studies in noncancer populations have pointed to the complexity of the chemoprevention approach. An unexpected high frequency of lung cancer was found in the intervention arms of two major placebo-controlled trials of ß-carotene in populations of predominantly cigarette smokersthe Alpha-Tocopherol, Beta-Carotene (ATBC) Cancer Prevention Study and the Beta-Carotene and Retinol Efficacy Trial (CARET) (18,19). In a third large double-blind study of 22071 healthy males, who were mainly nonsmokers, again no preventive effect of long-term (12 years) supplementation with ß-carotene was observed (32). In this study, an increased incidence of lung cancer associated with ß-carotene prescription was not observed, which led to the conclusion that ß-carotene might elicit adverse effects only in smokers (33). Recent animal experiments (34) seem to confirm this suggestion. In addition, in the EUROSCAN Study, a negative effect of the prescription of retinyl palmitate or N-acetylcysteine on the incidence of second primary tumors cannot be excluded. The fact that fewer second primary tumors were seen when the N-acetylcysteine and retinyl palmitate were combined, however, suggests an artifact, perhaps caused by the multiplicity of analyses and a consequent increase in the probabilities of error.
In the 1980s when the EUROSCAN Study was planned, comparative trials with traditional clinical end points were considered the best means to test candidate chemopreventive agents. In the light of current knowledge, it might be questioned at what stage large-scale, randomized studies should be initiated. Recent developments in molecular biology have provided the opportunity for carefully designed developmental protocols through which potential chemopreventive agents could be guided through phase I and II studies using intermediate end points that could lead to a more rational selection of agents for comparative studies (35).
Carcinogenesis is a multistep process occurring over many years, with a latent period (i.e., the period between the start of carcinogenesis and the occurrence of clinical cancer) that has been estimated to be at least 10 years long. Therefore, subjects in cancer prevention trials, such as the EUROSCAN Study, should be followed for periods of at least 10 years to reach definite conclusions.
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APPENDIX: PARTICIPANTS IN THE EUROSCAN STUDY |
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Data management and statistics: A. Kirkpatrick (European Organization for Research and Treatment of Cancer [EORTC] Data Center, Brussels, Belgium); O. Dalesio, J. Dijkstra, and H. van Tinteren (The Netherlands Cancer Institute, Amsterdam); and R. Parentela (Istituto dei Tumori, Milan, Italy)
Advisor: S. Piantadosi (The Johns Hopkins Hospital, Baltimore, MD)
The study took place during the chairmanships of G. B. Snow and J.-L. Lefebvre (EORTC Head and Neck Cooperative Group) and J. G. McVie, N. van Zandwijk, and G. Giaccone (EORTC Lung Cancer Cooperative Group).
The participants who collaborated in the EUROSCAN Study are, in order of number of patients accrued in the study, as follows: G. B. Snow, M. P. Copper, and N. de Vries (Free University, Amsterdam, The Netherlands); G. J. Hordijk and H. Lubsen (Academic Hospital, Utrecht, The Netherlands); U. Pastorino, C. Grandi, M. Infante, and P. Salvatori (Ist Nazionale per la studio dei Tumori, Milan, Italy); F. J. M. Hilgers, A. J. M. Balm, and N. van Zandwijk (The Netherlands Cancer Institute, Amsterdam); J. Jerman (University of Ljubljana, Slovenia); I. Spasova (Institute of Respiratory Diseases, Prague, Czechoslovakia); R. G. J. R. A. Vanderschueren (St. Antonius Ziekenhuis, Nieuwegein, The Netherlands); F. Lunghi (Monselice Hospital, Padua, Italy); J. Castella (Hospital de la Santa Creu I Sant Pau, Barcelona, Spain); G. Chiesa and M. Maioli (Ospedale Niguarda Ca Granda, Milan, Italy); G. P. M. ten Velde (Academic Hospital Maastricht, The Netherlands); M. Maffioli and R. Piantanida (Ospedale di Circolo, Varese, Italy); H. Maier (Universität Heidelberg, Germany); H. Szpirglas (Centre Hospitaliere Universitaire Pitié Salpétrière, Paris, France); J. P. van Meerbeeck (Universitair Ziekenhuis Antwerpen, Edegem, Belgium); A. Dundar (Gulhane M. Medical Academy, Ankara, Turkey); J. Pawlega, M. Krzysztof, and K. Krzemieniecki (Institut Onkologii, Krakow, Poland); P. Giannobi (Nuovo Ospedale San Gerardo, Monza, Italy); L. Barzan (Centro di Riferimento Oncologico, Aviano Pordenone, Italy); E. Jassem (Medical Academy of Gdánsk, Poland); Z. Skacel (2nd Clinic for Tuberculosis and Chest Diseases, Prague, Czechoslovakia); V. M. S. A. Vieira (Hospital Pulido Valente, Lisbon, Portugal); M. Virag (Klinici Bolnicki Centar, Zagreb, Croatia); G. Andry (Institut Jules Bordet, Brussels, Belgium); F. M. L. H. G. Palmen (St. Elizabeth Ziekenhuis, Tilburg, The Netherlands); C. Domenge (Institute Gustave Roussy, Villejuif, France); F. Cianfriglia (Istituto Regina Elena, Rome, Italy); G. Scagliotti (Universita di Torino, Orbassano, Italy); S. Staemars (Mutterhaus der Borromaerinnen, Trier, Germany); A. Personeni (Ospedali Riuniti di Bergamo, Italy); T. S. van der Werf (Akademisch Ziekenhuis, Groningen, The Netherlands); C. Berardi (Ospedale di Garbagnate Milanese, Milan, Italy); P. Drings (Thoraxklinik Rohrbach, Heidelberg, Germany); B. Cottier (Clatterbridge Hospital, Merseyside, U.K.); K. Bujko (Oncology Centre Institute, Warszawa, Poland); G. Ralza (Clinica ORL, Trieste, Italy); S. J. Brockmeier (Klinikum rechts der Isar, Munich, Germany); T. Lewinski (M. Slodowska-Curie Cancer Center, Warszawa, Poland); P. Espana (Clinica Puerta de Hierro, Madrid, Spain); R. Bastus (Hospital de Mutua de Terrassa, Barcelona, Spain); A. Ravaioli and E. Pasquini (Ospedale Civile Rimini Div Oncologia, Italy); M. Clerici (Ospedale San Carlo Borromeo, Milan, Italy); J.-M. Brechot (Hôtel-Dieu de Paris, France); W. Bergler (Klinikum der stadt Mannheim, Germany); J.-L. Lefebvre (Centre Oscar Lambert, Lille, France); G. S. Kho (Dijkzigt Hospital, Rotterdam, The Netherlands); J. Dolensky (Thomayer's Teaching Hospital, Prague, Czechoslovakia); F. van Breukelen (Spaarne Ziekenhuis, Haarlem, The Netherlands); and X. Panis (Centre Jean Godinot, Reims, France).
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NOTES |
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The EUROSCAN Study was funded by support from the European Organization for Research and Treatment of Cancer (EORTC) to the EORTC Data Center and from The Netherlands Cancer Institute to the Biometrics Department and by three separate grants from the European Commission-Directorate General V-Programme "Europe Against Cancer." Financial support for meetings was received from Zambon (Milan, Italy).
Zambon provided N-acetylcysteine, and Mucos (Geretsried, Germany) provided retinyl palmitate.
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Manuscript received July 19, 1999; revised March 29, 2000; accepted April 13, 2000.
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