Van Zandwijk et al. (2000): EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer

Reference ↗
Title	EUROSCAN, a Randomized Trial of Vitamin A and N-Acetylcysteine in Patients With Head and Neck Cancer or Lung Cancer
Topic	Vitamin A (beta-carotene)
Author	van Zandwijk, N, Dalesio, O, Pastorino, U, de Vries, N, van Tinteren, H
Year	2000
Journal	Journal of the National Cancer Institute
DOI	https://doi.org/10.1093/jnci/92.12.977

Brief summary

In this study, 4 groups of head and neck tumor or lung cancer patients after radiotherapy and/or tumor surgery were compared with each other. One group received vitamin A, one group received N-acetylcysteine (NAC, a chemical agent with mucolytic properties), one group received vitamin A and NAC and a control group received nothing except radiotherapy/surgery. Comparing the two groups that received vitamin A with the other two groups, there were no significant differences in the occurrence of first events such as recurrence, second primary tumor or death, in overall survival over a five-year period and in the time until the occurrence of second primary tumors. However, the fewest second primary tumors occurred in the group that had only received radiotherapy and/or surgery. Significantly more adverse events were reported in the groups receiving vitamin A than in the group receiving NAC alone. A disadvantage of this study is that there was no blinding (i.e. investigators/patients know which group they belong to), that there were more treatment dropouts in the vitamin A groups and that the reporting quality in this study was poor in some cases. Among other things, the results were reported in a very confusing and mixed way.

In dieser Studie werden vier Gruppen mit Kopf-Hals-Tumor- oder Lungenkrebs-Patienten nach Radiotherapie und/oder Tumoroperation miteinander verglichen. Eine Gruppe bekam Vitamin A, eine Gruppe N-Acetylcystein (NAC, ein chemischer Wirkstoff mit schleimlösenden Eigenschaften), eine Gruppe Vitamin A und NAC und eine Kontrollgruppe nichts außer Radiotherapie/Operation. Vergleicht man jeweils die beiden Gruppen, die Vitamin A bekommen haben, mit den anderen beiden Gruppen, fanden sich keine bedeutsamen Unterschiede bezüglich des Auftreten erster Ereignisse wie Rezidiv, zweiter Primärtumor oder Tod, bezüglich des Gesamtüberlebens in einem Zeitraum von fünf Jahren und bezüglich des Zeitraums bis zum Auftreten von zweiten Primärtumoren. Die wenigsten zweiten Primärtumoren tauchten jedoch in der Gruppe auf, die nur Radiotherapie und/oder Operation erhalten hatten. In den Gruppen mit Vitamin A wurden bedeutsam mehr unerwünschte Nebenwirkungen berichtet als in der Gruppe, die nur NAC erhalten hat. Ein Nachteil dieser Studie ist, dass keine Verblindung stattfand (d.h. Untersuchter/Patienten wissen, welcher Gruppe sie angehören), dass es in den Vitamin A Gruppen mehr Therapieabbrecher gegeben hat und dass die Berichtqualität in dieser Studie teilweise schlecht war. So waren unter anderen die Ergebnisse sehr verwirrend und durcheinander berichtet.

Study Design

Prospective / Retrospective Prospective: forward-looking, examples include clinical trials, cohort studies, and long-term observational studies;</br>Retrospective: backward-looking, relying on existing data, examples include case-control studies and retrospective cohort studies	Prospective
Monocentric / Multicentric Monocentric: conducted in one center/ hospital; </br>Multicentric: conducted in multiple centers/ hospitals	Multicentric
Blinding No: Open, all parties are aware of group assignments;</br>Single: one party is unaware of group assignments (generally participants);</br>Double: two parties are unaware of group assignments (generally the participants and the researchers); </br>Triple: concealing group assignment from additional parties	No
Is randomized	Yes
Cross-over Participants alternate between different treatment groups or conditions over a specified period, allowing each participant to serve as their own control	No
Number of arms	4

Study characteristics

Inclusion criteria	- Non-small-cell lung cancer (stages pT1–2, N0–1, and T3N0), cancer of the larynx (Tis, T1–3, and N0–1), or cancer of the oral cavity (T1–2 and N0–1) - Performance status 0–2 - Treated with curative intent
Exclusion criteria	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
N randomized	2592
Analysis PP: Per Protocol analysis, i.e. only participants included who adhered to the study protocol.</br>ITT: Intention-to-treat analysis, i.e. all randomized participants included regardless of any drop-outs or changes in assignment.</br>mITT: modified Intention-to-treat analysis can refer to analyses in which participants with missing outcome data are excluded or it can refer to analyses in which only participants who received at least one treatment dose are included. In this case, participants dropped out of the study prematurely for reasons unrelated to the treatment.	PP Analysis
Specifications on analyses	Event-free survival, time to second primary tumor, and survival curves were constructed by the Kaplan–Meier technique and were compared by the log-rank test. 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.
Countries of data collection	Italy, Netherlands
LoE Level of evidence	1b Oxford 2009
Outcome timeline Data collection times	T0: Baseline Follop-up: at least 2 years after randomization

Characteristics of participants

Setting Refers to cancer therapy setting.</br>- Curative therapy: aims to completely eradicate a disease and achieve a full recovery; </br>- Neo-adjuvant therapy: form of curative therapy, given before the primary treatment for cancer (usually surgery); </br>- Adjuvant therapy: form of curative therapy, given after the primary treatment for cancer (usually surgery); </br>- Palliative therapy: focuses on providing relief from symptoms and improving the quality of life for patients, without necessarily targeting the underlying disease; </br>- Active surveillance: involves close monitoring of disease progression without any intervention (typically used for prostate cancer);</br>- No therapy setting: Patients who completed therapy/are currently not in cancer treatment, cancer survivors.	No therapy setting
Types of cancer "Other Cancers" means that only a subpopulation was specified, but further unspecified cancer types were included	Head and Neck Cancers - Oral Cancer, Head and Neck Cancers - Laryngeal Cancer, Lung Cancer - Non-Small Cell Lung Cancer
Cancer stages Early Stage: generally refers to cancer that is localized to the area where it started, mostly stages I and II;</br>Advanced Stage: cancer that has spread beyond its original site, mostly stages III and IV, with stage IV indicating distant metastasis	Early Stage, Advanced Stage
Specifications on cancer stages	Per arm, n stage I/n stage II/n stage III: - vit. A: 395/167/85 - NAC: 371/176/95 - vit. A + NAC: 376/182/85 - control: 382/184/77
Comorbidities	NI
Current cancer therapies	No therapy
Specifications on cancer therapies	3.4% of patients received chemotherapy in addition to local treatment Time between radiotherapy/surgery and randomization (month) - vit. A group: < 2: 51%; 2-12: 32%, > 12: 17% - NAC group: < 2: 52%; 2-12: 30%, > 12: 17%, missing: 1% - vit. A and NAC group: < 2: 49%; 2-12: 36%, > 12: 15% - control group: < 2: 49%; 2-12: 34%, > 12: 17%
Previous cancer therapies	Surgery, Chemotherapy, Radiation therapy
Gender	Mixed
Gender specifications	13% female, n (male/female) per arm: - vit. A: 563/84 - NAC: 556/86 - vit. A + NAC: 560/83 - control: 559/82
Age groups	Adults (18+)
Age groups specification	Median (range): 61 (19-91), per arm: - vit. A: Median 61 (23-83) - NAC: 61 (28–86) - vit. A + NAC: 61 (23–83) - control: 60 (19-91)

Arms

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	638
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	12 (no clear indication of exact numbers)
Drop-out reasons	No clear indication of exclusion reasons
Intervention	Vitamine A (retinyl palmitate)
Dosage and regime	1st year: retinyl palmitate (300,000 IU) 1x/day 2nd year: retinyl palmitate (150,000 IU) 1x/day
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	730
Side effects / Interactions	Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss) Severe side effects (grade 3/4) - Gastrointestinal: 32 - Skin: 50 - Malaise: 5 - Temporary increase in liver enzymes: 2 - Hypercholesterolemia: 2 - Bone pain: 2 - Other: 15

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	637
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	8 (no clear indication of exact numbers)
Drop-out reasons	No clear indication of exclusion reasons
Intervention	N-acetylcysteine (NAC)
Dosage and regime	600mg NAC 1x/day
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	730
Side effects / Interactions	Typical: symptoms of the digestive tract (especially dyspepsia) Severe side effects (grade 3/4) - Gastrointestinal: 44 - Skin: 11 - Malaise: 2 - Temporary increase in liver enzymes: 1 - Other: 3

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Intervention
Number of participants (arm) N randomized	640
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	9 (no clear indication of exact numbers)
Drop-out reasons	No clear indication of exclusion reasons
Intervention	Vitamine A (retinyl palmitate) and N-acetylcysteine (NAC) combined
Dosage and regime	- Retinyl palmite (300 000 IU daily for 1 year followed by 150 000 IU for the 2nd year) - N-acetylcysteine (600 mg daily for 2 years)
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	730
Side effects / Interactions	Typical: mucocutaneous side effects (dryness, desquamation, itching, bleeding, hair loss), symptoms of the digestive tract (especially dyspepsia) Severe side effects (grade 3/4) - Gastrointestinal: 47 - Skin: 43 - Malaise: 1 - Temporary increase in liver enzymes: 3 - Hypercholesterolemia 3 - Bone pain 2 - Other: 8

Arm type Active control: group receives active treatment; </br>Passive control: for example treatment as usual, waiting control, no treatment	Passive control
Number of participants (arm) N randomized	633
Drop-out Number of participants who left the study for any reason or did not provide information on every data collection date	15 (no clear indication of exact numbers)
Drop-out reasons	No clear indication of exclusion reasons
Intervention	None
Dosage and regime	NA
One-time application	No
Duration in days For long-term interventions, the number of days is an estimation.</br>A value of -999 indicates that the exact duration cannot be extracted from the study due to ambiguous or incomplete information. See Outcome timeline or Dosage and regime for further information.	730
Side effects / Interactions	NA

Outcomes

Tumor progression

Outcome type As specificed by the authors	Primary
Outcome specification	Time to second primary tumor (SPT)
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall - No significant difference for number of SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.173 - No significant difference for number of tobacco-associated SPTs between (vit. A group and vit. A+NAC group) vs. (NAC group and control group) controlled for NAC: p=0.978 - Interaction with NAC: p = 0.039 i.e. difference between vit. A vs. no vit. A in terms of time period differed depending on whether NAC was additionally given or not - When comparing all four arms, number of SPT in arm D lowest: SPT in general p = 0.025, tobacco-associated SPT p = 0.174

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

PFS (Progression-Free Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	No recurrence/SPT/death
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall No significant difference for number of first events (recurrence/SPT/death) within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.672

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

OS (Overall Survival)

Outcome type As specificed by the authors	Primary
Outcome specification	NI
Type of measurement	Observation
Results during intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	NA
Results after intervention - Results during intervention means that the time of data collection is during or shortly after the period of the intervention (e.g. on the last day or a few days after). The results therefore still relate to the direct effects of the intervention.</br>- Results after intervention means there is a longer break between the time of data collection and the end of the intervention, e.g. more than a week. The results relate more to long-term effects.</br>- If a categorization in Results during vs. after intervention is not possible (e.g. survival data), the results are summarized under Results after intervention under the headline "Overall".	Overall No significant difference for number of deaths within 5 years between (vit. A group and vit. A+NAC group) vs. (NAC group and control group): p=0.925 Interaction (for NAC) not significant, i.e. no influence of NAC on results

Risk of Bias Assessment: Cochrane RoB tool 2.0
Bias arising from the randomization process	?
Bias due to deviation from intended intervention (assignment to intervention)	?
Bias due to deviation from intended intervention (adhering to intervention)	NA
Bias due to missing outcome data	?
Bias in measurement of the outcome	?
Bias in selection of the reported result	?
Other sources of bias	?
Overall RoB judgment	?

Funding and Conflicts of Interest

Funding	Funded by the European Organization for Research and Treatment of Cancer (EORTC), the Netherlands Cancer Institute, the European Commision Financial support for the meetings: Zambon (Italy) Provision of the preparations: N-acetylcysteine: Zambon; retinyl palmitate: MUCOS Pharma GmbH & Co. KG (Germany)
Conflicts of Interest	NI

Further points for assessing the study

Sample

Power analysis performed	?
- Sample size corresponds to power analysis	?
- Reasons for insufficient sample size based on power analysis	?
If no power analysis performed: at least moderate sample size (n >= 30 per arm)	?
Ethnicity mentioned	?

Alternative Explanation

Other explanations for an effect besides the investigated intervention	?
- Possibility of attention effects	?
- Possibility of placebo effects	?
- Other reasons	?

Statistics

Correct use of parametric and non-parametric tests Testing for normal distribution only necessary if parametric tests are used, NI: use of parametric tests without report of normal distribution testing	?
Correction for multiple testing	?
Measurement of compliance	?
Consistent reporting in numbers (figures, flowchart, abstract, results)	?
Comprehensive and coherent reporting	?
Cross-over	?
- Sufficient washout period	?
- Tested for carry-over effects	?
- Tested for sequence effects	?

Interpretation of results

Effect sizes reported (clinical vs. statistical significance)	?
Side effects systematically recorded	?
Side effects considered in result interpretation	?
Ethics votum	?

Additional Notes

PRO:

• Large sample according to power analysis

CONTRA:

• No blinding
• No p-values for baseline group differences -> at least descriptively partially different
• More treatment dropouts in vitamin A groups (vit. A: 26%/vit. A+NAC: 25% vs. NAC: 18%; p < 0.001)
• Very unclear reporting, only very few p-values reported overall