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Japanese Journal of Clinical Oncology Advance Access originally published online on April 24, 2009
Japanese Journal of Clinical Oncology 2009 39(6):367-375; doi:10.1093/jjco/hyp031
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© The Author (2009). Published by Oxford University Press. All rights reserved

A Comprehensive Comparative Study on the Characteristics of Colorectal Cancer Chemotherapy

Yasuhiro Inoue, Yuji Toiyama, Koji Tanaka, Chikao Miki and Masato Kusunoki

Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan

For reprints and all correspondence: Masato Kusunoki, Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, 2-174 Edobashi, Tsu, Mie 514-8507, Japan. E-mail: kusunoki{at}clin.medic.mie-u.ac.jp

Received January 9, 2009; accepted March 12, 2009


   Abstract
TOP
 Abstract
INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Objective: Analyses were performed to assess whether the use of chemotherapeutic agents or regimens against colorectal cancer (CRC) differed among countries, especially the United States (USA), the European Union (EU) and Japan.

Methods: The data source for this study was the IMS Health, Oncology AnalyzerTM. We utilized data on the use of anticancer drugs and follow-up information for patients with CRC from April 2006 to March 2007, collected from the USA, the EU (G5: France, Germany, Italy, Spain and the UK) and Japan. A total of 102 502 patients were enrolled.

Results: Wide differences were found in the actual regimens adopted by each region and nation. In other words, the concept of oncologist-related variability in chemotherapy for CRC was clearly seen. Factors such as a nation's historical characteristics and the healthcare policies of respective governments, including drug approval and cost-effectiveness, also appeared to have roles. However, comparisons of 5-year relative survival rates from population-based cancer registries in the USA, the EU and Japan showed that survival rates for CRC in the three regions did not differ widely, despite differences in the actual use of medical therapy. This may suggest that regional usage trends for anticancer regimens were optimal, although the application of chemotherapy was not the intentional standardization.

Conclusions: Global information exchanges regarding oncologist-related factors along with global evidence could result in patient survival being prolonged by the establishment of intentional standardized treatments suited for regional characteristics.

Key Words: colorectal cancer • chemotherapy • oncologist-related factor


   INTRODUCTION
TOP
 Abstract
 INTRODUCTION
PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Approximately 1 million new cases of colorectal cancer (CRC) were diagnosed in 2002 (9.4% of the world's total), and mortality is about half that of the incidence worldwide (approximately 529 000 deaths in 2002) (1). CRC is a major health problem in the western world and the second most common cause of death due to cancer (2).

To improve outcomes, the vast majority of patients with CRC receive chemotherapy with one or more of several agents presently approved for treatment in the relevant setting. During the past decade, the role of chemotherapy for CRC has expanded considerably, although surgery remains the mainstay of treatment. Initially dominated by bolus injections of 5-fluorouracil (5-FU), chemotherapy for CRC has progressed considerably through biochemical modulation of the 5-FU effect by leucovorin (LV) (3), development of infused 5-FU/LV regimens (4,5) and introduction of two new cytotoxic drugs: irinotecan and oxaliplatin (6–9). The median overall survival has increased from approximately 1 year in patients receiving bolus or continuous infusion 5-FU-based treatment (3), to between 14.8 and 20.1 months for combinations of 5-FU and irinotecan (3–6) or oxaliplatin (7,8) as the first-line treatment of metastatic disease. With more data available on the recent introduction of molecular-targeted agents (cetuximab and bevacizumab), there are now many treatment options to choose from. Thus, decisions regarding the optimal chemotherapy for patients with advanced CRC have become more complex with the availability of multiple effective agents. In addition, no straightforward choice can be made that provides any patient with the optimal applications of current chemotherapy.

Among the global evidence relating to treatment approaches for CRC, randomized controlled trials (RCTs) are the first choice in the development of standard chemotherapy protocols. In fact, this methodology has contributed significantly in achieving longer overall survival through CRC chemotherapy. However, we wondered whether a discrepancy might exist between the global evidence and actual use of CRC chemotherapy, because the evidence is mainly obtained from oncologists at specialized hospitals. Patient patterns at oncological centers may produce a population that differs from the general population who undergo chemotherapy at non-specialized community hospitals. In addition, several biases stemming from the experience and training of the oncologist, individual preferences, or the medical or social condition of the patients may influence the assessment of patients who undergo medical therapy for CRC.

An understanding of the actual trends in worldwide chemotherapy for CRC is needed to identify the best choice of chemotherapy, even after the global evidence has been established. Until date, however, comparative study of the regional characteristics of CRC chemotherapy around the world, especially in actual usage, has been lacking. This analysis was performed to assess whether the actual use of CRC chemotherapy agents or regimens differs among countries, especially the United States (USA), five nations of the European Union (EU) and Japan. We also discuss the current and future directions in chemotherapy for CRC.


   PATIENTS AND METHODS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
Data Sources
The data source for this analysis was the Oncology AnalyzerTM, which is a trademark of IMS Health. Oncology Analyzer provides insight into the oncology market of seven countries: the USA, the EU G5 (France, Germany, Italy, Spain and the UK) and Japan. It is an easy-to-use market research tool that has been designed to monitor various cancer treatments and therapies. It segments patients by indication, stage and line of therapy to provide an understanding of patient pathways, prescribers, products, prescribing initiation and treatment practice patterns. In Europe (EU G5) and Japan, Oncology Analyzer tracks the usage of chemotherapy, hormonal therapy, radiotherapy, surgery and supportive therapies. Patient data are recorded and collected using paper diary studies. In the USA, Oncology Analyzer tracks chemotherapy and supportive therapy usage. Patient data are collected from the electronic medical record systems used in physicians' offices.

Oncology Analyzer reports over 100 000 patient records annually from across the world. These records, which are collected from approximately 2000 physicians across seven countries, provide full treatment history from diagnosis to present day and include surgery, radiotherapy, chemotherapy, hormonal therapy and supportive care reports. Table 1 shows the key cancers covered in the Oncology Analyzer database.


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  		Table 1. Cancers covered in the Oncology Analyzer database

 
Sampling Methodology
Data for the EU and Japan are collected via a survey methodology in which physicians complete data collection forms for a number of patients per quarter. Based on their workload, physicians are asked to provide case histories for the last 5–25 patients they have seen and are requested not to provide the same patient's details twice in any 12-month period. Data for the USA are collected electronically from more than 625 oncologists using the IntelliDose® clinical software application, which captures the treatment decisions and details of 32 000 patients annually, creating a database of detailed information on the medical oncology care process. Data collection covers all aspects of the patient's chemotherapy treatment, from diagnosis of the cancer, assignment therapy, date of therapy and details of the therapy administered, to full demographics that include stage of the disease at diagnosis and at relapse. Regular reporting by a panel of physicians in each country provides stability in the data. Total annual samples comprise over 100 000 patient case histories across the seven countries. Physicians are recruited from key hospitals and oncology centers, and requested to provide details. The physicians recruited have different levels of experience, ranging from a registrar to a consultant, that expounds different attitudes and approaches to treatment and prescribing behaviors. In the EU and Japan, the panel consists of over 1300 physicians, with an average of 200 per country. The target coverage is 70% of major cancer centers in each country. In the EU, patients are treated mainly at public hospitals (approximately 80%), but several other types of hospitals are also involved (clinic, private, academic, military, etc.). In Japan, physicians practice in general hospitals (49%) and specialized hospitals (51%). In the USA, over 625 physicians are distributed across nine regions of the country. The data are collected from electronic medical records, ensuring that the panel is constant. The physicians practice primarily in community hospitals and clinics (42%), private settings (31%), academic institutions (25%) and military hospitals (2%).

Methodology of Sales Comparison
We used the multinational integrated data analysis system (IMS Health, MIDAS®) for sales comparison of the various chemotherapeutic agents used in treatment of patients with CRC. MIDAS represents the integration, viewing and analysis platform for IMS Health audits. It links all local products internationally using standards that enable cross-country comparison. The sales data in MIDAS are calculated by the equation ‘sales = amount x unit price’. The pricing information in each nation differs with respect to the average wholesale selling price, medicine cost and manufacturing cost. As a result, the sales data compiled for each nation also differ in terms of the price level. In the current study, we used three price levels—manufacturer level (MNF), trade level (TRD) and public level (PUB)—for sales analysis. MNF is used in France, Germany, Italy and Spain. TRD is used in both the EU and the USA. PUB is used in Japan. In addition, to compare price levels internationally, we used individual coefficients that depended on each nation.

Using the worldwide data obtained from IMS Health, the global trends in chemotherapy for CRC were reviewed in a joint research project with the Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine. All investigations were approved by our Institutional Review Board.


   RESULTS
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
DISCUSSION
 Funding
 Conflict of interest statement
 References
 
To understand the outline of global trends in cancer chemotherapy, we first analyzed the worldwide sales of anticancer drugs from 2004 to 2007 using MIDAS. Figure 1 shows sales figures for anticancer drugs commonly used in the treatment of CRC, as well as other cancers including lung, and head and neck cancer. In the USA, the sales figures for bevacizumab are the highest, and its sales have been increasing over the past 2 years. Next came oxaliplatin followed by cetuximab; however, the sales of these agents have remained steady. In the EU, oxaliplatin has been the undisputed sales leader, and its sales are on a continuous rise. The second spot is shared by bevacizumab, cetuximab and irinotecan which have all had nearly equal sales. In Japan, S-1 has been the sales leader, followed by tegafur/uracil (UFT). The sales of oxaliplatin have increased since the past 3 years although it still held the fourth place in sales ranking in 2007, whereas those of irinotecan have remained low.


Figure 1
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  		Figure 1. Sales figures for anticancer drugs commonly used in the treatment of CRC, as well as other cancers. CRC, colorectal cancer; US (a), EU5 (b) and Japan (c).

 
Next, a total of 102 502 patients in seven nations were enrolled in our study from April 2006 to March 2007 (Table 2). Of this total, 33 264 patients were from the USA, 59 188 patients from the EU and 10 050 patients from Japan. Among the102 502 patients, 13 021 (3771 patients in the USA, 7598 patients in the EU and 1652 patients in Japan) had CRC. Table 3 shows the distribution of CRC cases by each stage in each nation. There were no significant differences in stage distributions among the seven nations.


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  		Table 2. Number of cases of CRC listed in the IMS Oncology Analyzer database

 

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  		Table 3. CRC distribution by stage

 
Figure 2a shows the uses of first-line chemotherapy for stage IV CRC in the USA. Molecular-targeted drugs are aggressively used in the USA. Capecitabine, the only oral fluorinated pyrimidine approved in the USA, is also frequently administered. Figure 2b shows the uses of second-line chemotherapy after the first-line FOLFOX plus bevacizumab. Even in second-line chemotherapy, molecular-targeted drugs are frequently used. In the EU, FOLFOX regimen is most popular with first-line chemotherapy for stage IV CRC (Fig. 3a). Figure 3b shows the uses of second-line chemotherapy after the first-line FOLFOX regimen. The uses of FOLFIRI regimen are frequently used. In the EU, molecular-targeted drugs are used less often, whereas 5-FU/LV is popular. Figure 4 shows the uses of first-line chemotherapy for stage IV CRC in Japan. Oral fluoropyrimidine is widely used in Japan. Frequent usage of S-1 is another characteristic of Japan. FOLFIRI constitutes 90% of all second-line regimens used after the first-line FOLFOX regimen. The use of FOLFOX is spreading rapidly, whereas irinotecan remains infrequently used. Figure 5 shows the worldwide use of first-line chemotherapy for stage III CRC. The FOLFOX regimen is widely used in both the USA and the EU. However, the use of capecitabin is characteristically found in the USA and of 5-FU/LV in the EU. In Japan, unlike the USA and the EU, oral fluoropyrimidines such as UFT, UFT/LV and S-1 are widely used.


Figure 2
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  		Figure 2. (a) Use of first-line chemotherapy for stage IV CRC in the USA. (b) Use of second-line chemotherapy after the first-line FOLFOX plus bevacizumab. USA, United States; 5-FU, 5-fluorouracil; LV, leucovorin.

 

Figure 3
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  		Figure 3. (a) Use of first-line chemotherapy for stage IV CRC in the EU. (b) Use of second-line chemotherapy after the first-line FOLFOX regimen. EU, European Union.

 

Figure 4
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  		Figure 4. Use of first-line chemeotherapy for stage IV CRC in Japan. UFT, tegafur/uracil.

 

Figure 5
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  		Figure 5. Stage III CRC first-line chemotherapy regimen. CAPOX, capecitabine/oxaliplatin; 5'DFUR, doxifluridine.

 
We also investigated whether chemotherapy regimens differed between countries of the EU from January to December 2006. Figure 6 shows the use of anticancer drugs for CRC in five nations of the EU. For both adjuvant and therapeutic chemotherapy, there are differences in the uses of regimens among nations of the EU.


Figure 6
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  		Figure 6. Use of anticancer drugs for CRC in five nations of the EU.

 
Furthermore, the actual use of CRC chemotherapy may depend on the healthcare policies of the respective governments. Figure 7 shows the application or approval of anticancer drugs for CRC in the USA, the EU and Japan. Drug approval of several anticancer agents in Japan is lagging behind the USA and the EU.


Figure 7
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  		Figure 7. Timeline of application or approval of anticancer drugs for CRC in the USA, the EU and Japan.

 

   DISCUSSION
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
Funding
 Conflict of interest statement
 References
 
The current concept of evidence-based medicine applied in oncology is the hallmark of good clinical practice. Progress in CRC chemotherapy, seen in the development of multiple effective regimens derived from RCT outcomes, has led to increasingly complex treatment decisions. An important determinant of the overall length of survival appears to be the number of active agents that a patient receives. A retrospective study of several clinical trials demonstrated that overall survival duration was greatest in patients who had received 5-FU/LV, irinotecan and oxaliplatin during the course of their treatment (4–7,10–15). Exposure to all three active agents during the course of disease improves survival to approximately 20 months, the current benchmark. The recent emergence of molecular-targeted monoclonal antibody therapies, with proven efficacy against metastatic CRC, has also provided significant improvements in outcomes for patients. Furthermore, the introduction of oral forms of 5-FU is an important development for treatment with oral fluoropyrimidines such as capecitabine, UFT/LV and S-1, and will make protracted, concurrent treatments with drugs much easier. Consequently, the distinctions between various chemotherapy methods are no longer very clear. Most patients with advanced CRC receive multiple treatment regimens, with therapies changed to either optimize responses or as a consequence of toxicity, patient preference or disease progression.

The main objective of chemotherapy for CRC is to optimize survival, time without toxicity and quality of life; therefore, therapies need to be individualized in a way that allows each regimen to complement this objective. However, it is not possible to make definitive choice that will provide patients with optimal applications of current chemotherapy regimes. A solution would be to make treatment decisions based on comprehensive information obtained from both specialized and non-specialized hospitals, as observed in this study.

We believe that the current study represents the first effort to compare regional variations in the actual use of CRC chemotherapy. We assembled prospective databases from the USA, the EU and Japan. After comparisons, we found wide differences in the actual regimens adopted by region and nation, even if the information given in the guidelines did not differ widely (Table 4) (16–21). In other words, the concept of oncologist-related variability in chemotherapy for CRC was formally recognized around the world. We think that oncologist-related factors may be derived from the historical characteristics of each nation as well as from the healthcare policies, including drug approval and cost-effectiveness, of the respective governments.


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  		Table 4. The actual trends in worldwide chemotherapy for CRC

 
Historical characteristics were actually identified as factors favoring use of infused 5-FU/LV in the EU, molecular-targeting agents in the USA and oral fluoropyrimidines in Japan. Oral fluoropyrimidines such as UFT, doxifluridine (5'DFUR) and S-1 are used in Japan, despite the lack of evidence related to the use of oral fluoropyrimidines in CRC treatment. This may be the result of there being few medical oncologists in Japan, with most patients being treated by surgeons. We confirmed that the healthcare policies of the respective governments were also factors. For example, drug approval in Japan occurs much more slowly than in the USA or the EU, and the National Institute for Health and Clinical Excellence in England and Wales determined that both bevacizumab and cetuximab were not recommended for first- or second-line treatment of CRC because of their low cost-effectiveness, although both agents are licensed in the UK.

Interestingly, despite differences in the actual use of medical therapy for CRC, the comparison of 5-year relative survival rates obtained from population-based cancer registries in Japan (7 prefectures), the USA (9 registries in the SEER Program) and the EU (22 countries in the EUROCARE study) revealed that survival rates for CRC in the three regions were not widely different (Table 4) (22–24). However, many factors as well as chemotherapy affect the survival of patients with CRC. It is conceivable that the different use of medical therapy resulted in similar survivals, suggesting that each regional trend in the usage of anticancer regimens was an optimal one, although the application of chemotherapy was not the intentional standardization. In addition to evidence based on RCTs, increasing mutual understandings of regional characteristics could result in intentionally standardized treatments suited for regional characteristics, and thus survival of patients could be prolonged.

Oncologists now have a substantial number of regimens to select from when designing a treatment strategy for CRC. Individual preferences and the medical or social conditions of the patient may have important roles in the choice of a particular treatment. Based on these concepts, oncologists must continue to use clinical judgment suited to regional characteristics to balance efficacy with toxicity and cost in the treatment of metastatic CRC. We believe that worldwide analyses of oncologist-related factors for cancer therapy will contribute to the advent of more effective therapeutics.


   Funding
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
Conflict of interest statement
 References
 
This study was supported by IMS Japan K.K.


   Conflict of interest statement
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
References
 
None declared.


   Acknowledgments
 
We thank Tsutomu Miyazawa, Tamayo Hirouchi and Yoshifumi Kondo for analyzing the data.


   References
TOP
 Abstract
 INTRODUCTION
 PATIENTS AND METHODS
 RESULTS
 DISCUSSION
 Funding
 Conflict of interest statement
 References
 
1 Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002. CA Cancer J Clin (2005) 55:74–108.[Abstract/Free Full Text]

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14 Grothey A, Sargent D, Goldberg RM, Schmoll HJ. Survival of patients with advanced colorectal cancer improves with the availability of fluorouracil-leucovorin, irinotecan, and oxaliplatin in the course of treatment. J Clin Oncol (2004) 22:1209–14.[Abstract/Free Full Text]

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24 Kato H, Sobue T, Katano K, Saito Y, Tsukuma H, Saruki N, et al. The Editorial Board of the Cancer Statistics in Japan. Cancer Statistics in Japan 2007. (2007) Tokyo: Foundation for Promotion Cancer Research (FPCR). 46.


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