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Current Status of Oral Anticancer Drugs in Japan

Pharmaceuticals and Medical Devices Evaluation Center, National Institute of Health Sciences, Ministry of Health and Welfare, Tokyo, Japan

To the Editor: Recently, the Journal of Clinical Oncology published several articles outlining the promising future of oral anticancer drugs.^1-4 Although oral anticancer drugs are now receiving more attention than ever in the United States, probably because of health insurance constraints, the situation in Japan is different. Here, many oral anticancer drugs have been marketed for a number of years.⁵ Table 1 shows that 18 of 49 oral anticancer drugs are approved in both Japan and the United States as of July 1999. Nineteen are approved in Japan but not in the United States, and 12 are approved in the United States but not in Japan. The United States was first to approve 16 of 18 mutually available drugs, approving them a median 54.9 months ahead of Japanese approval, whereas two drugs (tretinoin and toremifene) were first approved by the Japanese.

There are several characteristics of the approval status of Japanese oral anticancer drugs. The first thing to note is that drugs are sometimes licensed for tumors in many organs, partly because in Japan anticancer drugs are approved if they achieve objective tumor shrinkage, including a partial response, and because data from randomized, comparative phase III trials are not, in principle, essential for anticancer drug approval. The second point is that there is no discrepancy between the indication on the label and the indication covered by the insurer. This is because the Japanese health finance system is based upon fee-for-service reimbursement under a uniform national price schedule⁶ (the current National Health Insurance reimbursement tariff for oral anticancer drugs is shown in Table 1 and subscribers and their dependents have to pay a fee that is 20% to 30% of the drug's price (copayment) when obtaining prescriptions from hospitals or pharmacies). In contrast, in the United States, there are differences between the Food and Drug Administration (FDA)–approved indications and those covered by the insurer; for example, the Medicare coverage for anticancer chemotherapy is based not only on the FDA-approved indications (ie, the indications on the label) but also on those included in the USP Drug Information, AHFS Drug Information, or quality academic medical journals. The final point to note is that many fluoropyrimidine derivatives are approved for use. The second and third best-selling anticancer drugs in Japan, including those for infusion, are the oral fluoropyrimidine derivatives tegafur-uracil and doxifluridine. This unique situation may be largely due to the fact that fluorouracil-sensitive gastrointestinal tumors prevail in Japan, and stomach cancer had been the leading cause of cancer-related death for many years before 1993. Also, there is a long history of prescribing oral fluoropyrimidine derivatives in an adjuvant setting, mainly by surgeons, without firm clinical evidence of any survival benefit. In addition, these agents are usually prescribed in order to relieve vague anxieties in both physicians and patients about cancer recurrence.

Because of these problems related to oral anticancer drugs in Japan, I was very interested to see the recent increase in the number of publications describing oral anticancer drugs in academically high-ranking medical journals, including this one, and I would like to point out several problems regarding the Journal of Clinical Oncology's recent articles.

First, I would like to make it clear to readers that Gan To Kagaku Ryoho is the same journal as the Japanese Journal of Cancer and Chemotherapy (Jpn J Cancer Chemother). These titles have been referred to separately in reference lists.³ This journal carries articles written in Japanese, with only concise abstracts in English.

Since the reviews^2,3 cited many Japanese articles, I am afraid that selection bias might have occurred because the cited Japanese journals form only a small proportion of the many cancer-related journals published in Japan. Accordingly, it might be desirable for authors to include information on the sources and methods of selection used to choose the data reviewed. Considering the recent trend for preference of systematic reviews instead of narrative reviews, and the fact that the Journal publishes both systematic⁷ and narrative review articles, I would like to know the Journal's editorial policy for review articles.

Another point which was not discussed in detail in one review² was the difference in response criteria for gastric cancer between Japan and the United States/Europe. In Japan, there is a long history of tumor response evaluation in which the primary tumor site is regarded as measurable. In 1985, the Japanese Research Society of Gastric Cancer formally adopted evaluation criteria for the primary tumor site based on barium roentgenography and/or endoscopy findings. Almost all gastrointestinal oncologists have used these criteria for many years, even before 1985, when submitting their research articles to Japanese journals, whereas they have usually excluded data on the primary tumor site (or have been requested to do so by the journal reviewers) when submitting manuscripts to journals published in Western countries. Furthermore, Japanese clinical researchers have usually excluded nonassessable cases from the denominator when calculating the response rate. Therefore, readers should be aware of the need for caution when interpreting the data presented in the review² and any other articles from Japan.

The West Japan Study Group for Lung Cancer Surgery has recently reported the results of a randomized clinical trial comparing two courses of cisplatin + vindesine + mitomycin and 1 year of tegafur-uracil with no adjuvant treatment in 229 patients with completely resected stage I or II non–small-cell lung cancer.⁸ The 5-year survival rate for the surgery-only arm was reported to be 71.1% (stage I, 75.1%; stage II, 50.0%), not significantly different from that (76.8%) for the adjuvant chemotherapy arm.^8,9 This prognosis for the surgery-only arm was far better than that for the same population in the group's previous study (stage I, 60.9%; stage II, 23.1%) reported in the Journal.^4,10 I would like to know whether the authors found any difference in the prognostic factors of each surgery-only arm. Furthermore, their subgroup analysis, published in a Japanese journal in the same year as the Journal's publication, showed that a survival benefit was observed only in stage IIIA patients,¹⁰ although in their Journal article, the authors commented that tegafur-uracil therapy was useful for treatment of stage I and II, as well as IIIA, disease.⁴ In contrast, the subset analysis in their most recent article showed that adjuvant chemotherapy improved the survival of pT1N0 patients.⁸ These facts cast doubt on their evidence supporting the benefit of adjuvant chemotherapy with oral fluoropyrimidine derivatives for non–small-cell lung cancer.

Finally, financial interest and its disclosure in scientific publications are now receiving more attention than ever,¹¹ and I understand that the Journal requires full disclosure. Although it is well known among Japanese clinical researchers that the West Japan Study Group for Lung Cancer Surgery is largely supported by a drug company, I wonder why the authors did not disclose this fact in their article.⁴ In addition, I also wonder whether the authors of a review failed to disclose a conflict of interest, since they used unpublished data on file from the company,² the credibility of which we, as readers, cannot evaluate. I understand that financial interest in itself does not imply any bias in the results of a paper and should not disqualify it from publication.¹¹ However, the aforementioned reluctance to disclose industry involvement by Japanese clinicians may be one of the reasons why clinical trials of new drug applications ("Chiken" in Japanese) and industry-sponsored clinical trials in the postmarketing setting have acquired such a bad academic and public reputation in Japan.

In conclusion, I hope that readers will take all these problems and facts into account when appraising articles describing Japanese oral anticancer drug clinical trials. Furthermore, it should be noted that the aforementioned problems related to Japanese clinical trials, especially for new drug applications, are rapidly being resolved due to the legal obligation of Good Clinical Practice and Good Post-Marketing Surveillance Practice, the establishment of the Pharmaceuticals and Medical Devices Evaluation Center and the Organization for Pharmaceutical Safety and Research as part of the ongoing reform of the Japanese new drug application review system,⁵ and because the notion of "evidence-based medicine" is becoming more widespread.

NOTES

The opinions expressed in this letter are solely those of the author and does not necessarily reflect the views of any government agency.

REFERENCES

1. DeMario MD, Ratain MJ. Oral chemotherapy: Rationale and future directions. J Clin Oncol16:2557-2567, 1998[Abstract]

2. Takiuchi H, Ajani A: Uracil-tegafur in gastric carcinoma: A comprehensive review. J Clin Oncol16:2877-2885, 1998[Abstract]

3. Sulkes A, Benner SE, Canetta RM: Uracil-Ftorafur: An oral fluoropyrimidine active in colorectal cancer. J Clin Oncol16:3461-3475, 1998[Abstract]

4. Wada H, Hitomi S, Teramatsu T, et al: Adjuvant chemotherapy after complete resection in non–small-cell lung cancer: West Japan Study Group for Lung Cancer Surgery. J Clin Oncol14:1048-1054, 1996[Abstract/Free Full Text]

5. Fujiwara Y: MD reviewers' role in the new anticancer drug approval process in the newly established Japanese regulatory agency, PMDEC (Pharmaceuticals and Medical Devices Evaluation Center). Jpn J Clin Oncol28:653-656, 1998[Free Full Text]

6. Yoshikawa A, Bhattacharya J, Vogt WB (eds): Health Economics of Japan: Patients, doctors, and hospitals under a universal health insurance system. Tokyo, Japan, University of Tokyo Press, 1996

7. Fossati R, Confalonier C, Torri V, et al: Cytotoxic and hormonal treatment for metastatic breast cancer: A systematic review of published randomized trials involving 31,510 women. J Clin Oncol16:3439-3460, 1998[Abstract]

8. Wada H, Miyahara R, Tanaka F, et al: Postoperative adjuvant chemotherapy with PVM (cisplatin + vindesine + mitomycin C) and UFT (uracil + tegafur) in resected stage I-II NSCLC (non-small cell lung cancer): A randomized clinical trial—West Japan Study Group for lung cancer surgery (WJSG). Eur J Cardiothorac Surg15:438-443, 1999[Abstract/Free Full Text]

9. West Japan Study Group for Lung Cancer Surgery: Postoperative adjuvant chemotherapy for non-small cell lung cancer: West Japan Study Group for lung cancer surgery—Third study [in Japanese]. Proc Jpn J Lung Cancer36:574, 1996 (abstr)

10. West Japan Study Group for Lung Cancer Surgery: A randomized controlled postoperative adjuvant chemotherapy trial of CDDP + VDS + UFT and UFT alone in comparison with operation only for non-small cell lung carcinomas: Second study [in Japanese]. Haigan (Jpn J Lung Cancer)36:863-871, 1996

11. Krimsky S, Rothenberg LS: Financial interest and its disclosure in scientific publications. JAMA280:225-226, 1998[Abstract/Free Full Text]

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