Treating IIA/B Seminoma With Combination Carboplatin and

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Treating IIA/B Seminoma With Combination Carboplatin and
VOLUME
27
䡠
NUMBER
12
䡠
APRIL
20
2009
JOURNAL OF CLINICAL ONCOLOGY
Study of Newspaper Reports
Regarding Clinical Trials in Japan
C O R R E S P O N D E N C E
A
E a ch P a pe r
T otal
450, 000
1, 600, 000
TO THE EDITOR: Clinical trials are necessary for the development
400,000
1,400,000
of new drugs and treatment methods. To conduct clinical trials
smoothly, it is essential to improve public awareness of clinical trials.
Accordingly, information regarding clinical trials must be disclosed
and provided to the public in an understandable form. However, in
Japan, 50% of patients in general and 70% of all participants in clinical
trials have stated that the amount of information regarding clinical
trials is scarce,1 and people perceive the information services related to
clinical trials to be deficient.
The mass media, including newspapers and television broadcasts, are effective means of providing information to the public. In
Japan, 8.3% of the television audience is equivalent to approximately 3
million people,2 and the circulation of major newspapers ranges from
2.2 million to 10 million per day. Therefore, the use of mass media
facilitates the provision of information to a large number of people at
once. On the other hand, cooperation from mass media is necessary to
improve public awareness of medical care.3-5 However, many physicians appear to be dissatisfied with the media reports regarding medical care.2 Therefore, it cannot be said that the relationship between
these two parties is favorable.
To conduct clinical trials effectively, cooperation from
mass media is essential. However, there have not been any
studies that have systematically investigated mass media reports
regarding clinical trials, so the situation thereof is unknown.
We used the most up-to-date newspaper database to examine
the situation of reports on clinical trials in the major Japanese newspapers.
Our study was directed at the five major newspapers in Japan (ie,
Asahi, Mainichi, Yomiuri, Sankei, and Nihon Keizai). The total number
of subscribers to these newspapers is 27 million per day. The largest
newspaper database in Japan, Nikkei Telecom, was used to obtain
article information. This database incorporates articles from
almost all newspapers that are issued in Japan, including every
article in the five major newspapers since 1992. First, using a
thesaurus search of Igaku Chuo Zasshi (Japan Medical Abstracts), we extracted words related to clinical trials to define the
following words as keywords: investigational agent, preclinical
study, drug screening, nonclinical test, clinical trial, sponsored
study, clinical protocol, prospective study, comparative test,
blind study, phase I study, phase II study, phase III study, phase
IV study, postmarketing surveillance, randomized clinical trial,
Good Clinical Practice, Good Laboratory Practice, clinical research coordinator, institutional review board, and clinical investigator. To investigate the number of articles related to
clinical trials and the reported content, the articles published by
the five major Japanese newspapers from 1992 to 2007 were then
examined for the number of articles that contained these keywords, annual change, and content.
350,000
Journal of Clinical Oncology, Vol 27, No 12 (April 20), 2009: pp 2099-2108
1,200,000
M
300,000
1,000,000
A
Y
250,000
800,000
200,000
S
600,000
150,000
N
100,000
400,000
50,000
200,000
0
06
20
02
04
20
20
00
20
98
19
96
19
94
19
19
92
0
B
400
1, 600
350
1,400
300
1,200
250
1,000
200
800
150
600
100
400
50
200
0
06
20
04
20
02
20
00
20
98
19
96
19
94
19
19
92
0
Fig 1. (A) Total number of articles in five major newspapers. (B) Number of
clinical trial–related articles in five major newspapers. Bar, five newspapers taken
together; A, Asahi; M, Mainichi; Y, Yomiuri; S, Sankei; N, Nihon Keizai.
Figure 1A shows the annual change in the total number of articles
in the five major newspapers. Although the total number of articles
had been increasing from the early 1990s, there was almost no change
after 2000. After 2000, the total number of articles in the Yomiuri,
Asahi, and Mainichi newspapers was approximately three times that in
Nihon Keizai and Sankei. Figure 1B shows the change in the number of
clinical trial–related articles in the five major newspapers. The proportion of the number of clinical trial–related articles among the total
number for all five major newspapers temporarily increased to
0.167% in 1996 (Fig 2). The number of such articles in Nihon Keizai
increased after 2000. The number of such articles in Sankei reached a
slight peak in 2002. Most of the articles in Nihon Keizai were related to
the performance of pharmaceutical companies, such as the development of new drugs. For the four other papers, the proportion of the
number of articles in the other periods remained constant at about
0.07%. Figure 3 shows the peak year for the appearance of each
keyword. The major keywords appeared most frequently in 1994 and
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2099
No. of Clinical Trial-Related Articles (%)
Correspondence
0.30
Y
0.25
N
0.20
S
0.15
0.10
0.05
A
M
0.00
1992
1994 1996
1998
2000
2002
2004
2006
Year
Fig 2. Ratio of clinical trial–related articles to the total number of articles. Bar,
five newspapers taken together; A, Asahi; M, Mainichi; Y, Yomiuri; S, Sankei; N,
Nihon Keizai.
1996. The peak year for the appearance of words related to the methodology of clinical trials, such as phase and protocol, was 1994. The
peak year for the appearance of words such as the Ministry of Health,
Labour and Welfare; lawsuit; Pharmaceutical Affairs Law; clinical trial;
ethics; and others was 1996.
Our study revealed that in the newspapers, clinical trial–related
articles occupied a certain space but accounted for a small proportion
of total articles. In the five major newspapers, the percentage of clinical
trial–related articles among all articles was approximately 0.07%,
0.1000
10
15
14
11
13
1
12
12
5
Percent
0.0100
2
3
4
7
9
16
0.0010
8
20
06
20
04
20
02
00
20
19
98
19
96
19
94
19
92
0.0001
Fig 3. Peak year of the ratio of articles containing each keyword to the total
number of articles. (yellow circle) phase-related words; (blue square) procedurerelated words; (red ⫻) political words; (blue triangle) others. 1, phase I study; 2,
phase II study; 3, phase III study; 4, phase IV study; 5, preclinical test; 6,
randomization; 7, protocol; 8, Good Clinical Practice; 9, coordinator; 10, Ministry
of Health, Labour and Welfare; 11, Pharmaceutical Affairs Law; 12, guideline; 13,
ethics; 14, investigational drug; 15, lawsuit; 16, doctor-led model clinical trials.
2100
which means that two or three articles were disseminated per day. As
the aging of Japanese society progresses, public awareness of medical
care has been increasing. Many clinicians seem to think that this has
resulted in an increasing number of clinical trial–related reports in the
major newspapers. However, despite these anticipations, the proportion of such articles remained substantially unchanged in the four
newspapers other than Nihon Keizai, except for a temporary peak in
1996. That is, despite the efforts of the medical community, the number of clinical trial–related articles did not increase in the general
readership newspapers. Considering the fact that many people obtain
medical information from newspapers, it would be difficult to believe
that there have been recent improvements in public awareness of
clinical trials.
Significant differences were observed in the percentage of clinical
trial–related articles by newspaper company. In particular, it is interesting that Nihon Keizai recently showed an increasing percentage of
clinical trial–related articles. From 2002 to 2007, the percentage of
clinical trial–related articles became more than double the percentage
in the 1990s. Nihon Keizai is an economic paper, so it regards pharmaceutical companies as a growing field in Japan, and thus reports on
clinical trials from the perspective of investment and pharmaceutical
industry performance. Health care professionals rarely view clinical
trials from the perspective of investment and economic growth.
Therefore, there may be some discrepancies between their perspective
and that of the public.
The number of clinical trial–related articles increased sharply in
1996. This was because in the same year, HIV-tainted blood scandals6
and cases of drug-induced Jacob’s disease7 became social problems.
Furthermore, in 1994, misconduct in a clinical trial for sorivudine8 led
to a social problem, resulting in an increased number of related articles. These facts conform to the tendency of mass media to prefer to
deal with incidents and new events. In 1994 and 1996, there was an
increased appearance of words related to the methodology of clinical
trials such as phase II and phase III as well as keywords such as the
Ministry of Health, Labour and Welfare; lawsuit; Pharmaceutical Affairs Law; clinical trial; and ethics. Therefore, it is believed that people
were exposed to information regarding the methodology of clinical
trials and the administrative role of pharmaceutical affairs via news
reports on medication scandals and misconduct in clinical trials. It is
undeniable that the reports of major newspapers on clinical trials in
relation to medication scandals and misconduct could possibly have
an influence on the formation of negative public impressions regarding clinical trials.
On the other hand, in Japan, the system of clinical trials has
developed greatly since 2000, and the Pharmaceutical Affairs Law was
amended considerably in 2002.9,10 Our study found that the appearance of certain keywords reached a peak during that time: coordinator
in 2002, and doctor-led model clinical trials in 2005. During this
period, there were no major medication scandals or incidents of misconduct. These keywords were used in articles regarding amendments
of the system of clinical trials. It should be noted here that the number
of reports with these keywords (coordinator and doctor-led model
clinical trials) was approximately 10% that of reports on medication
scandals in 1996. This fact means that the administration of pharmaceutical affairs and discussions regarding the system of clinical trials
may be reported in the newspapers, but only with a small amount of
text. Therefore, in comparison with the topics of medication scandals
and misconduct, it may be difficult to promote public understanding
© 2009 by American Society of Clinical Oncology
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JOURNAL OF CLINICAL ONCOLOGY
Correspondence
regarding the systemic reform of clinical trials. Taking these facts into
consideration, to enhance public understanding regarding clinical
trials, it may be important to utilize means of providing information
other than newspapers, which often emphasize medication scandals
and misconduct.
Our study shows that clinical trials are topics that the major
newspapers report. However, many of the newspaper reports emphasize the performance of pharmaceutical companies and incidents of
misconduct, such as medication scandals, while providing insufficient
information regarding the system of clinical trials. It is recommended
that health care professionals fully understand these characteristics of
the major newspapers.
Morihito Takita
Division of Social Communication System for Advanced Clinical Research, The
Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Hiroto Narimatsu
Division of Social Communication System for Advanced Clinical Research, The
Institute of Medical Science, The University of Tokyo; Division of the Strategic
Outcome Research Program for Cancer Control, Ministry of Health, Labour
and Welfare Commission, Japan Cancer Society, Tokyo, Japan
Tomoko Matsumuira and Yukiko Kishi
Division of Social Communication System for Advanced Clinical Research, The
Institute of Medical Science, The University of Tokyo, Tokyo, Japan
Tamae Hamaki, Yuko Kodama, Koichiro Yuji, Yuji Tanaka,
and Masahiro Kami
Division of Social Communication System for Advanced Clinical Research, The
Institute of Medical Science, The University of Tokyo, Tokyo, Japan
AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
The author(s) indicated no potential conflicts of interest.
REFERENCES
1. Saito K, Kodama Y, Ono S, et al: Current status of quality in Japanese
clinical trials. Contemp Clin Trials 26:503-509, 2005
2. Matsumura T, Yuji K, Nakamura T, et al: Possible impact of the NHK special
questioning cancer treatment in Japan on clinicians’ prescriptions of oxaliplatin.
Jpn J Clin Oncol 38:78-83, 2008
3. Grilli R, Ramsay C, Minozzi S: Mass media interventions: Effects on health
services utilisation. Cochrane Database Syst Rev 1:CD000389, 2002
4. Tian Y, Robinson JD: Media use and health information seeking: An
empirical test of complementarity theory. Health Commun 23:184-190, 2008
5. Bala M, Strzeszynski L, Cahill K: Mass media interventions for smoking
cessation in adults. Cochrane Database Syst Rev 1:CD004704, 2008
6. Swinbanks D: Documents confirm delays in Japanese HIV blood scandal.
Nature 379:760, 1996
7. Dillner L: BSE linked to new variant of CJD in humans. BMJ 312:795, 1996
8. Swinbanks D: Deaths bring clinical trials under scrutiny in Japan. Nature
369:697, 1994
9. Saito K, Kodama Y, Ono S, et al: Quality of Japanese clinical trials
estimated from good clinical practice audit findings. Am J Ther 13:127-133, 2006
10. Saito K, Kodama Y, Ono S, et al: Reliability of Japanese clinical trials
estimated from GCP audit findings. Int J Clin Pharmacol Ther 46:415-420, 2008
Naoko Murashige
DOI: 10.1200/JCO.2008.21.3967; published online ahead of print at
www.jco.org on March 16, 2009
Ministry of Health, Labour and Welfare, Aide of the Minister, Health Sector
Reform Office, Tokyo, Japan
■ ■ ■
Treating IIA/B Seminoma With
Combination Carboplatin
and Radiotherapy
TO THE EDITOR: Garcia-del-Muro et al1 recently reported results
from treating 72 patients with IIA/B seminoma with combination
chemotherapy, giving a 5-year progression-free survival of 90% (95%
CI, 82% to 98%) and overall survival of 95% (95% CI, 89% to 100%).
Concluding that combination chemotherapy avoided long-term risks
associated with radiotherapy (RT) they suggested this as an alternative treatment.
While accepting these results, we remain unconvinced that this is
a significant step forward in treating this patient group. In addition to
the significant acute toxicity, combination chemotherapy for testicular cancer leads to a well-documented two-fold increased risk of cardiovascular disease.2-4 Chemotherapy is also (as for RT) associated
with significant increases in second malignancy. Overall the odds ratio
favors RT: subdiaphragmatic RT increases the risk of major late complication (second malignancy or cardiovascular disease) by 1.8-fold
(95% CI 1.3- to 2.4-fold), whereas chemotherapy increases this risk by
1.9-fold (1.4- to 2.5-fold).5 Further the risk of second malignancy after
subdiaphragmatic RT may be reduced by as much as half if treatment
is restricted to the para-aortic region.6
Historically, the main stay of treatment has been RT to the paraaortic and ipsilateral pelvic lymph nodes. A review of 313 patients
from seven studies with IIA/B seminoma treated with RT alone sugwww.jco.org
gested 22 relapses: a crude relapse rate of 7%,7 though the risks may be
higher in stage IIB disease and after relapsing on surveillance; 5-year
relapse-free survivals (RFSs) from our previous report of 80 patients
treated with RT alone were 84.9% for IIA and 69.4% for IIB.8 We agree
that improving outcomes achieved by RT is a worthwhile goal, but
believe this can be achieved without resorting to initial combination
chemotherapy. We have previously published a series of 33 patients
with seminoma stage IIA/B treated with carboplatin (one or two
cycles) and RT between 1989 and 1997, achieving a 5-year RFS of
96.9%.8 Subsequently, since 1997, we have treated a further 29 patients
(13 IIA and 16 IIB, including three patients who had relapsed while on
surveillance for stage I disease). Twenty-eight patients received carboplatin dosed at area under curve (AUC) 7, one patient AUC6. With
respect to RT, all patients received 30Gy in 15# MPD administered
with 6 MV photons, over 3 weeks, commencing 4 weeks after administration of the carboplatin. RT fields treated the para-aortic (from
D10/11 interspace to L5/S1) lymph nodes. The first five patients
treated in this series received a boost to the involved node of 5Gy in
3 fractions over 3 days. No relapses have been observed with a median
follow-up of 3.4 years (range, 0.6 to 7.5 years), giving a 3-year RFS of
100% (95% CI, 75.3% to 100%). One patient required surgical removal of residual radiological abnormality via retroperitoneal lymph
node dissection. Histology from this tissue revealed elements of differentiated teratoma and histological review of the original orchidectomy
specimen in the light of this revealed differentiated teratoma in the
primary tumor.
In stage I disease, the efficacy of carboplatin in safely eliminating
clinically undetectable metastatic disease has been demonstrated in a
© 2009 by American Society of Clinical Oncology
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