Japanese Journal of Clinical Oncology, 2016, 46(1) 23–30

doi: 10.1093/jjco/hyv123
Advance Access Publication Date: 12 August 2015
Review Article

Review Article

Urologic cancer in Japan: role of Japan at the

frontier of issues in Asia
Hideyuki Akaza*
Strategic Investigation on Comprehensive Cancer Network, Interfaculty Initiative in Information Studies/Graduate

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School of Interdisciplinary Information Studies, The University of Tokyo, Meguro-ku, Japan
*For reprints and all correspondence: Hideyuki Akaza, Strategic Investigation on Comprehensive Cancer Network, Interfa-
culty Initiative in Information Studies/Graduate School of Interdisciplinary Information Studies, The University of Tokyo,
4-6-1, Komaba, Meguro-ku, Tokyo 153-8904, Japan. E-mail: [email protected]
Received 28 June 2015; Accepted 12 July 2015

Abstract
The characteristics of urological cancer in Japan can be summarized in the following points. (i) As the
onset of this type of cancer is typically seen in elderly patients, it is becoming a major social issue in
Japan that has already become an aging society. (ii) Many diverse treatment methods are available
and a response is required that prioritizes quality of life. (iii) Although vigorous research and devel-
opment efforts into new drugs are being carried out on a global level, resulting in beneficial medical
agents becoming more readily available, unless concepts relating to cost vs. effectiveness are further
developed and there is a real risk that medical systems and structures in their current form will be-
come unsustainable. (iv) Although at the current point there are no original large-scale clinical trials
being conducted in Asia, Japan has a wealth of experience of participating in many international joint
clinical trials and it is therefore an urgent and pressing challenge to organize joint clinical trials in
Asia and amass a body of knowledge that is unique to Asia. In view of this current situation and
given Japan’s position at the frontier of issues, it is important for Japan to take the initiative in
Asia in cooperating with other Asian nations in efforts to resolve and overcome various challenges.

Key words: prostate cancer, kidney cancer, bladder cancer, Japan

Introduction treatment in accordance with shared international criteria. The result

of these efforts has been that currently there are standard treatment
Until now, Asia has been characterized by significant differences in med-
guidelines available domestically and internationally for many types
ical standards, disparities in skills of medical practitioners and diverse
of cancer, meaning that treatment guidelines have been compiled
value sets among patients. It has been a region in which data do not lend
itself to simple comparisons and one in which cooperation in the med- and are in use. However, even with guidelines in place, it does not ne-
ical field has been difficult. While economic growth has been dramatic cessarily mean that all cancer patients can receive the same standar-
in recent years, the burden of history still looms large over the region, dized treatment. Guidelines are compiled in a way that takes into
with acute divisions surfacing between globalism and nationalism. account scientific (medical) evidence and various constraints. No mat-
Cancer is a disease that is closely related to various challenges in all ter how medically effective one kind of treatment may considered to
spheres of society, including politics, economy, foreign policy and cul- be, if there are circumstances in a country (or region or certain popu-
ture. In a sense it could be said that ‘cancer represents a mirror-image lation) that prevent the treatment considered most beneficial from
of society.’ being provided, it is impossible to provide treatment in accordance
In recent years, efforts have been implemented to standardize can- with the predetermined guidelines. The impact of these constraints is
cer treatment. These efforts have included initiatives to standardize immense. In the internet age all people around the world can readily
treatment methods in single countries and also attempts to standardize access information about treatment methods, regardless of national

© The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected] 23
24 Urologic cancer in Japan

borders. However, in the case that for whatever reason the treatment According to these statistics, in 2011 the highest cancer morbidity
about which information is provided online cannot be provided or re- rate among men was for stomach cancer, followed by prostate cancer.
ceived in the country or region in question, this creates personal dilem- Lung cancer was third, followed by bowel cancer. However, if
mas and stress for patients, families and medical practitioners alike. It fifth-placed colon cancer is combined with bowel cancer, together
is easy, therefore, to anticipate that such personal stresses will develop they would exceed the morbidity rate of stomach cancer. In terms of
into various wider social stresses (1,2). urological cancer, the morbidity rate is highest for prostate cancer,
In general, urological cancer significantly impacts the quality of life followed by renal cell carcinoma and bladder cancer. Among
(QOL) of patients in many cases, and in projects such as this one, women the highest morbidity rates are for breast, bowel, stomach
which aim to assess and compile information about the current status and lung cancer, but if both bowel and colon cancers were to be com-
in Asia and clarify various specific issues, it will also be important to bined, they would exceed the morbidity rate for breast cancer to take
consider Universal Health Coverage in Asia. the top spot. In terms of morbidity rates for women in urological
It is from just such a perspective that it is important to take a look cancer, renal cell carcinoma is 11.0 per 100 000 population, followed
at the current situation of urological cancer in Japan and engage in by bladder cancer at 7.6.
discussion about the way forward. In terms of cancer mortality rates, the ranking for men is as
follows: lung, stomach, bowel, liver, colon, pancreatic and prostate.
Mortality rates for renal cell carcinoma and bladder cancer are 9.1

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Who treats patients with urological cancer per 100 000 population and 8.6, respectively. For women, the mortal-
in Japan? ity rates for these two cancers are 4.7 and 3.7, respectively.
In cases diagnosed between 2000 and 2005, the relative 5-year
Treatment systems for urological conditions in Japan feature slightly
survival rates for prostate, renal cell and bladder cancers in men
different aspects to treatment systems in other fields of medical care. In
were 93.8, 66.9 and 76.5%, respectively. The survival rates for
contrast to fields that specialize in respiratory, digestive, circulatory and
women for renal cell and bladder cancer were 63.3 and 64.4%,
nervous systems, the field of urology covers both medical and surgical
respectively.
care simultaneously. Although the same can be said for gynecology,
dermatology, ophthalmology, oral surgery and otology, the proportion
of overall treatment accounted for by treatment of malignant tumors can Urological cancer in the context of the aging society
be understood to be the greatest in urology and gynecology. Figure 5 shows a comparative graph of the proportion of the population
Given that urology in Japan deals simultaneously with medical accounted for by people over the age of 65 in various regions of the
and surgical care, the treatment of malignant tumors is handled in world (5). As can be clearly seen, Japan has by far the highest propor-
much the same way as other urological conditions, which is different tion of persons over the age of 65, who in 2015 account for 25% of the
from the examination and care system for urological cancer practiced total population. The aging of society is also projected to advance in
in the USA. In the USA, urologists have conventionally been considered developing and emerging economies including China. Figures 6–8 de-
as one kind of specialist surgeon, with a trend toward concentrating pict the morbidity rates by age for various types of urological cancer
exclusively on surgical procedures. This trend toward specialization (http://ganjoho.jp/public/statistics/pub/statistics01.html). These graphs
was highly appraised economically and this led to further moves amply demonstrate that cancer prevalence is concentrated in the elderly
away from medical treatment methods, including cancer chemotherapy. population. Table 1 shows newly diagnosed cases of prostate cancer in
However, on the other hand it has been pointed out by some urologists, Japan in 2010 as surveyed by the Japan Prostate Cancer Study Group
including Paul Lange and others, that this move toward specialization (J-CaP), detailing the age of diagnosis and the clinical staging of the can-
has started to have the adverse effect of reducing interest in development cer (6). In this study, 81.7% of all cases were in men over the age of 65
trials for new drugs (3). and 33%, or one-in-three cases were in men over the age of 75. These
In contrast, in Japan, urologists have conventionally treated malig- figures show that in an aging society the morbidity rates for urological
nant tumors using both surgical and medical methods. Following the cancer are extremely high, with prostate cancer being most prevalent.
establishment of the Japanese Society of Medical Oncology, prepara- This situation requires serious consideration as a serious challenge for
tions were made for a platform that would support the development of society. Similar challenges are likely to be faced by other countries in
medical oncologists specializing in urological cancer (4). However, as Asia in the near future, including China and Korea, making it a shared
there is no national qualification system in place for urological oncol- issue for all countries. Measures to tackle urological cancer in Japan can
ogists, the system still remains unchanged, with urologists working to therefore be expected to be at the frontier of issues facing urological
provide all forms of urological cancer care. cancer in the countries of Asia in the near future, in both positive and
Japan can therefore be seen to have pursued the development of a negative aspects.
system that is distinct from that of the USA. From now, it will be
necessary to develop the system further, with efforts being required
to avoid pitfalls similar to those encountered by the US system. Present status and future direction of the
development of anti-cancer agents against
urological cancer
Epidemiological characteristics of urological
Table 2 shows a list of new anti-cancer drugs for malignant urological
cancer in Japan
cancer that have recently been approved by the US Federal Drug Ad-
Urological cancer in Japan ministration (FDA). From 2006, there was a wave of development of
The latest statistics from the Cancer Information Service (http:// molecular targeted drugs for renal cell carcinoma, followed by a devel-
ganjoho.jp/public/statistics/pub/statistics01.html) show the morbidity opment boom in agents for castration-resistant prostate cancer
rate (Fig. 1) and mortality rate (Fig. 2) for urological cancer in Japan (CRPC), which has continued to the present. What is important to
by gender, as well as the 5-year survival rate (Figs 3 and 4). note is that there has been a near total absence of new drugs for
 Jpn J Clin Oncol, 2016, Vol. 46, No. 1 25

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Figure 1. Incidence rate by cancer site (2011). Source: Center for Cancer Control and Information Services, National Cancer Center, Japan.

Figure 2. Mortality rate by cancer site (2013). Source: Center for Cancer Control and Information Services, National Cancer Center, Japan.

bladder cancer. In general, urological cancer includes renal cell, pros- cancer and highly metastasized non-seminomatous testicular cancer. It
tate, bladder and testicular cancer. Among these, the types that have is regrettable that in these fields there has not been significant progress
the poorest post-treatment life expectancy are muscle-invasive bladder in new drug development.
26 Urologic cancer in Japan

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Figure 3. Five-year relative survival rate by cancer site diagnosed in 2003–05 (male). Source: Center for Cancer Control and Information Services, National Cancer
Center, Japan.

Figure 4. Five-year relative survival rate by cancer site diagnosed in 2003–05 (female). Source: Center for Cancer Control and Information Services, National Cancer
Center, Japan.

However, in the field of bladder cancer there have been quiet Reiterating the point made above, what is important to note here is
attempts made in clinical development of various drug candidates the detrimental effect that the significant shift from urologists to med-
that include immune checkpoint inhibitors (7,8) and anticipation is ical oncologists has had in terms of the development of new drugs
mounting that in the near future there will be a wave of new drug devel- overseas. In general, there are many cases of urological cancer where
opment in the field of bladder cancer, similar to the waves of develop- surgery with curative intent can be used. However, in such cases the
ment seen for renal cell carcinoma and prostate cancer. primary issue is development of drug treatments that will function
 Jpn J Clin Oncol, 2016, Vol. 46, No. 1 27

Figure 8. Trends in age-specific incidence rate of prostate cancer (Japan, 2011).

Figure 5. Future trends of proportion of over 65 years old. Source: United

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Source: Center for Cancer Control and Information Services, National Cancer
Nations World Population Prospects. Center, Japan.

Table 1. Japan Prostate Cancer Study Group surveillance—newly

diagnosed prostate cancer in 2010 (Japan)

Variable %

Age ≤59 7.0

60–64 13.4
65–69 22.2
70–74 24.5
75–79 19.8
≥80 13.2
T factor T1 41.6
T2 35.7
T3 18.3
T4 4.3
Figure 6. Trends in age-specific incidence rate of bladder cancer (Japan, 2011).
N factor N0 91.2
Source: Center for Cancer Control and Information Services, National Cancer
N1 7.7
Center, Japan.
M factor M0 89.6
M1 10.5
Clinical Stage I 58.3
II 16.1
III 11.2
IV 13.6

Table 2. US Federal Drug Administration (FDA)-approved anti-tumor

agents in urology in the last 7 years

Year of FDA Renal cell Prostate Urothelial

approval carcinoma cancer cancer

2006 Sorafenib
2007 Temsirolimus
Sunitinib
Figure 7. Trends in age-specific incidence rate of kidney cancer (Japan, 2011).
Source: Center for Cancer Control and Information Services, National Cancer
2008 Degarelix
Center, Japan. 2009 Everolimus
Bevacizumab
Pazopanib
to prevent future reoccurrence or metastasis, or pre and/or post- 2010 Sipuleucel-T
surgical treatments that aim for a curative outcome. There are various Cabazitaxel
factors involved in the implementation of trials for such candidate 2011 Abiraterone
Denosumab
drugs, including the length of the trial period and ambiguity in deter-
2012 Axitinib Enzalutamide
mining results. However, early treatment of cancer by surgical meth-
2013 Alpharadin
ods is not within the so-called scope of medical oncologists, with the
28 Urologic cancer in Japan

Table 3. FDA-approved drugs for CRPC treatment

Estramustine* 1981 Ancient history

Strontium-89* 1993 Reduction in bone pain
Mitoxantrone/prednisone 1996 Reduction in pain
Samarium-153 1997 Reduction in bone pain
Zoledronic acid* 2002 Skeletal-related events
Docetaxel/prednisone* 2004 Prolonged survival
Sipuleucel-T 2010 Prolonged survival
Cabazitaxel/prednisone* 2010 Prolonged survival
Denosumab* 2010 Skeletal-related events
Abiraterone/prednisone* 2011 Prolonged survival
Enzalutamide* 2012 Prolonged survival
Abiraterone/prednisone* 2012 RPS/trend OS, etc.
Radium-223 dichloride 2013 Prolonged survival

*Approved drugs in Japan as of June 2015.

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Figure 9. US Federal Drug Administration-approved therapies —relationship
between OS and PFS hazard ratios. of these drugs was made contingent on the implementation of a survey
of all cases of use after their market release, which has resulted in
valuable clinical data on multiple cases being reported (13–15).
result being that under current conditions almost all of the trials that Phase III trials relating to fully human PD-1 immune checkpoint
are being planned by medical oncologists are limited to those for inhibitors in metastatic renal cell carcinoma are currently ongoing
advanced-stage cancer. Such new drug candidates aim to extend on a global level, including Japan (16,17). The primary endpoint of
patient life by several months, and are thus somewhat different from these trials is an extension in OS and results are pending.
actual clinical priorities.
Taking a look at the current international situation, we can see that
not only in the case of new drug development, but in almost all Prostate cancer
large-scale joint clinical trials, plans are being formulated in regions
In the field of prostate cancer, there has been much work done on the
outside Asia that at best include only a relatively small number of
development of anti-tumor drugs for CRPC (18–20).
Asian trial patients from limited countries and regions. Given the real-
Table 3 shows the chronology of anti-tumor drugs for CRPC
ities of the current situation it is therefore clear that urological cancer
approved in the USA.
specialists in Japan should play a more prominent role, given their
What should be noted here is that as of June 2015, only the five
wealth of experience with multi-center joint studies.
drugs marked with an asterisk in the table have been approved for
use in Japan.
Renal cell carcinoma As the advance of prostate cancer is predominantly through the
At the time of their initial development, cytokines attracted a great route of androgen action (21), it has been conventionally considered
deal of press attention as a wonder drug. In addition, clinical trials appropriate to provide drugs for androgen-sensitive cancer. However,
of IFN and IL-2 for renal cell carcinoma were implemented very quick- as the results of this type of treatment require considerable time before
ly in Japan, with approval being granted in Japan ahead of the USA. It they become ineffective, there has been a noticeable trend toward to set
may be due to this background, but the recommended cytokine dosage a clinical trial for developing new drug against CRPC patients, for
differed between Japan and the USA, with the disparity for IL-2 being which treatment results can be achieved in a relatively short timeframe.
particularly noticeable (9,10). Subsequently, however, the effects of Noticeable differences between Asian and western countries in morbid-
IL-2 and IFNα in the field of cancer failed to reach initial expectations. ity and mortality rates for prostate cancer have been noted (22). Various
It is no exception to say that cytokines are now mainly used only for contributing factors have been cited, including differences in the living
renal cell carcinoma in a limited number of cases (11). The 2000s saw environment and differences in diet in particular (23). In addition, in a
the upcoming of a second epoch-making era, in the form of the devel- comparative study between Japan and the USA of the treatment results
opment of molecular targeted drugs. There were successive successes for primary androgen depletion therapy, in which the same risk categor-
in Phase III trials of TKI and mTOR inhibitors. However, the need for ies were used in terms of patient characteristics (24); the results showed
calm and level-headed judgment on these drugs is evident in Figure 9. that despite the fact that the Japanese patients in the study were at higher
This graph shows the relationship between overall survival (OS) and risk and older aged, they demonstrated superior cause-specific survival
progression-free survival (PFS) hazard ratios from the results of (25), from which it was noted that there is a difference in sensitivity to
Phase III trials for renal cell carcinoma. With the exception of temsir- endocrine therapy in prostate cancer. In a registration study for endo-
olimus, for which the primary endpoint in the trial was OS benefit, crine therapy in prostate cancer, Japan is currently handling most of
while a primary endpoint of PFS benefit was proven for the drugs in the cases (26). This study has also been expanded into a joint research
the trial, in terms of the secondary endpoint of OS benefit no drugs project with other countries in Asia (27).
showed any demonstrable extension (12). In order to establish the pos- As for the prostate cancer, it is an important issue how to treat lo-
ition of these drugs in the clinical world in the future it will be neces- calized curable cancer, because recent spread of PSA test and longevity
sary to engage in an accurate evaluation of the benefit/risk and cost/ of Japanese males increased rapidly the incidence of localized prostate
effectiveness balance. With regard to sorafenib, sunitinib, everolimus cancer (Table 1). There are some treatment choices for this category of
and temsirolimus, which are the four drugs that have been newly ap- prostate cancer such as active surveillance, radical surgery and radical
proved for the treatment of renal cell carcinoma in Japan, the approval radiation therapy. Among radical surgery, the recent strong trend is
 Jpn J Clin Oncol, 2016, Vol. 46, No. 1 29

robot-assisted radical prostatectomy that is remarkably widespread in circumstances of Asia and ensures that they are fit for the purpose
Japan. This is also a big issue in the aspect of cost/efficacy consideration. for utilization in the Asian context. The third edition of the guidelines
on renal cell carcinoma and first edition on bladder cancer are current-
ly in the process of being compiled. The revised guidelines for prostate
Bladder cancer
cancer were completed in September 2013 and uploaded on the
Bladder cancer is one type of cancer that has the greatest impact on pa-
NCCN website at the beginning of 2014. The concept behind the com-
tient QOL. Radical cystectomy to totally remove cancer results in the
pilation of these guidelines is detailed in the guidelines themselves and
insertion of a urinary diversion, which is a direct and severe factor in
is accessible on the NCCN website.
reducing patient QOL. In addition, as prognosticators are relatively
well understood, such as muscle/non-muscle-invasive tumors and the
histological grade of tumor cells, it is possible for surgeons to make a Conclusion
decision on whether to perform a total cystectomy or use endoscopy Looking from the perspective of actions and approaches relating to the
to perform a transurethral resection (TUR). Current urgent challenges Global Health Agenda, it can be said that among the countries of Asia,
in the field of bladder cancer can be characterized as follows: (i) the need Japan was the first to incorporate medical knowledge and expertise
to thoroughly examine the suitability of a total cystectomy and expand from western countries and engage in its own development in the
the scope for preserving bladder functions; (ii) the need to engage in fur- field of medical care and research. One of the results of Japan’s suc-

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ther research of prognosticators and develop treatment techniques to cesses in the field of medical care has been its emergence as the world’s
achieve expanded scope for preserving bladder functions; (iii) the most aged society. Highly advanced medical technologies and an envir-
need to use TUR in principle for non-muscle-invasive bladder cancer onment in which it is possible to implement equality of care based on a
(NMIVBC) and preserve bladder functions, and also to improve treat- national health insurance system have contributed to the increased lon-
ment methods relating to post-surgical prevention of reoccurrence gevity of Japan’s population. However, the challenges that Japan cur-
inside the bladder and prevention of the progression of recurrent malig- rently faces will soon become the shared problems of Asia as a whole.
nant tumors; (iv) the development of biomarkers relating to reoccur- It is from this perspective that this article has examined Japan’s stance in
rence and malignant progression; (iv) the development of new anti- Asia in terms of cancer care in general and urological cancer specifically.
tumor drugs for progressive/metastatic lesions; and (vi) the formulation It is hoped that Japan’s efforts to find solutions to the various chal-
of a primary prevention strategy for bladder cancer. From the above lenges it faces will provide valuable lessons for the countries of Asia to
points, it can be discerned that bladder cancer is a field that requires avoid similar challenges in the future, or at least to mitigate challenges
a multidisciplinary approach. Since the 1980s many international con- through more effective countermeasures.
ferences have been held on the subject of bladder cancer (28), in which
Japanese urologists have played a leading role. In the course of such ac-
tions, multi-center joint research on intravesical chemotherapy for
Funding
NMIVBC has been carried out nationwide, which has amassed a This study was partially funded by the Ministry of Education, Culture,
great deal of knowledge (29,30). The clinical trial of BCG Tokyo-172 Sports, Science and Technology.
to prevent reoccurrence of bladder cancer is one of the successful out-
comes of the various research and actions that have been taken (31).
Conflict of interest statement
None declared.
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