S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer

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1 Breast Cancer Vol. 13 No. 2 April 2006 Case Report S-1 (TS-1) maintained complete response for approximately 10 years in a case of metastatic breast cancer Naruto Taira 1, Kenjiro Aogi 1, Shozo Ohsumi 1, Shigemitsu Takashima 1, Rieko Nishimura 2, Hiroyoshi Doihara 3, and Toshiaki Saeki 4 1 Departments of Surgery, and 2 Departments of Pathology, National Hospital Organization, National Shikoku Cancer Center, 3 Department of Cancer and Thoracic Surgery, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, 4 Department of Breast Surgery, Saitama Medical School Hospital, Japan We present a patient with pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 years after recurrence. A 51-year-old woman underwent modified radical mastectomy for left breast cancer in November Her cancer was postoperatively classified as pt2 pn0 M0 Stage IIA. As postoperative adjunctive treatment, tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) were given. During the administration period (30 months after surgery), a solitary pulmonary metastasis occurred. Three months after the start of S-1 (100 mg/body/day), the tumor disappeared on images. Thereafter she took S-1 orally for approximately 10 years, and the pulmonary metastatic focus maintained complete response. In addition, no recurrent focus was observed. The adverse events observed during S-1 treatment were nausea, low-grade neutropenia and pigmentation of fingers. All were mild, and S-1 could be continued. Our case illustrates two important characteristics of S-1. First, S-1 was effective even though this patient had a lung metastasis during adjuvant treatment with HCFU. S-1 is a combined formulation containing 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat), which inhibits an enzyme that metabolites 5-FU, dihydropyrimidine dehydrogenase (DPD). Therefore, high 5-FU concentrations are maintained with S-1, and S-1 may be effective in the patients who do not respond to other fluoropyrimidine agents. Second, since S-1 toxicity was mild, long-term treatment for approximately 10 years was possible. Since S-1 contains potassium oxonate (OXO; otastat), gastrointestinal toxicities, the main adverse events of 5-FU agents, could be reduced. The purpose of treatments for metastatic breast cancer is to maintain favorable quality of life (QOL), as well as to improve survival. S-1 could be a valuable agent for breast cancer treatments, since it showed clinical efficacy and mild toxicity, and can be given orally. Breast Cancer 13: , Key words: S-1, TS-1, metastatic breast cancer Introduction In a phase II study of S-1 using 110 patients with metastatic breast cancer, the response rate (RR) was 41.7%, and the median survival time (MST) was 872 days 1). The results of a previous phase II trial indicate that S-1 is well-tolerated and effective in metastatic breast cancer patients. We report a patient with a pulmonary metastasis from breast cancer who received S-1 (TS-1) and maintained complete response for approximately 10 Reprint requests to Naruto Taira, Department of Surgery, National Hospital Organization, Shikoku Cancer Center, 13 Horinouchi, Matsuyama-city, Ehime , Japan ntaira@shikoku-cc.go.jp Received March 18, 2005; accepted January 11, 2006 years after recurrence. Case Report A 51-year-old menopausal woman presented in August 1991 with a painless left breast mass. The patient was otherwise entirely healthy without any significant past or current medical problems. Physical examination revealed a cm, irregular shaped, firm, and poorly-defined mass at the upper lateral quadrant of the left breast. The lymph nodes were not palpably enlarged in the left axilla or neck. Primary breast cancer was diagnosed based on the clinical, radiologic and cytologic findings, and modified radical mastectomy 220

Breast Cancer Vol. 13 No. 2 April 2006 Fig 1 Histological pictures. Left: Histologic specimen of the breast tumor (hematoxylin-eosin stain) shows the features of invasive ductal carcinoma.

1994/7/2 1994/8/2 1994/10/4 Fig 2 Chest X-ray. Left: On July 2, 1994, before S-1 administration, a metastatic nodule 2.2 1.7cm in size was observed in the right middle lung field (black arrow).

2 Breast Cancer Vol. 13 No. 2 April 2006 Fig 1 Histological pictures. Left: Histologic specimen of the breast tumor (hematoxylin-eosin stain) shows the features of invasive ductal carcinoma. Right: Transbronchial lung biopsy histology shows atypical cells within the lymph vessels under the bronchial epithelium. The pulmonary nodule was a breast cancer metastasis. 1994/7/2 1994/8/2 1994/10/4 Fig 2 Chest X-ray. Left: On July 2, 1994, before S-1 administration, a metastatic nodule cm in size was observed in the right middle lung field (black arrow). Center: On August 2, one month after the start of S-1, a 60% reduction in tumor size ( cm) was observed (black arrow). Right: On October 4, three months after the start of S-1, the tumor completely disappeared. was performed in September Pathological examination of the resected specimens revealed invasive ductal carcinoma, lack of lymph node metastasis, and estrogen and progesterone receptor negativity (Fig. 1). According to the UICC- TNM classification, her cancer was pt2 pn0 M0 Stage IIA. Adjuvant therapy with tamoxifen and hexylcarbamoyl 1-5-FU (HCFU) was started. In April 1994, a small nodular lesion 1.0 cm in diameter in the right middle lung field was revealed by follow-up chest X-ray. During a followup period of about two months, the pulmonary nodule gradually enlarged to cm, which indicated malignant tumor (Fig. 2). On a radiologic image, primary lung cancer or pulmonary metastasis of breast cancer was suspected. Transbronchial lung biopsy was performed in May, and it was pathologically revealed that the pulmonary nodule was a breast cancer metastasis (Fig. 1). TAM and HCFU were stopped. Systemic close 221

3 Taira N, et al S-1 maintained complete response for 10 years in metastatic breast cancer 1994/7/2 2004/1/19 Fig 3 Chest CT. Left: On July 2, 1994, before S-1 administration, a metastatic nodule was observed. Right: On January 19, 2004, the tumor completely disappeared. The pulmonary nodule first disappeared on chest X-ray on October 4, The patient maintained complete response for approximately 10 years during which tramline shadow (white arrow) was followed by CT. investigations were performed, but no metastasis to other organs or bone was observed. Consent to participate in the clinical study of S-1 for metastatic breast cancer was obtained, and S-1 was started from July 11 with an intermittent dosing regimen (50mg twice daily for 4 weeks every 2 weeks). On August 2, a 60% reduction of the tumor size ( cm) was observed on chest X-ray. On October 4, the pulmonary nodule disappeared on chest X- ray (Fig. 2). Afterwards, the tramline shadow was followed with chest CT (Fig. 3). Systemic close investigations performed on January 19, 2004, showed no metastasis to other organs or bones, and S-1 was stopped on January 29. The adverse events observed during 82 treatment cycles over approximately 10 years were nausea, low-grade neutropenia during the early treatment phase and pigmentation in fingers. They were all mild (Grade 1) according to the National Cancer Institute s Common Toxicity Criteria Version 2.0. As of January 2005, no recurrence of breast cancer had been observed. Discussion This case was treated with adjuvant tamoxifen and HCFU. About 10 years previously, patients with hormone-receptor negative status were treated with tamoxifen at our institution, because it was thought that tamoxifen might still have a small, but statistically significant survival benefit in women with tumors lacking hormone-receptor expression 2). However, the most recent metaanalyses with longer follow-up and a larger sample size do not suggest a survival benefit in such patients 3). In addition, adjuvant treatments with oral fluoropyrimidine compounds were widely used at that time in Japan, although there was no clear evidence of statistically significant survival benefit. Recently, a pooled analysis of 6 randomized controlled trials suggests a survival benefit of an adjuvant oral fluoropyrimidine, UFT, in nodenegative breast cancer patients 4). Further clinical trials might be necessary to clarify the positioning of adjuvant oral fluoropyrimidine in node-negative breast cancer patients, in comparison with standard chemotherapy using agents such as cyclophosphamide, methotrexate and fluorouracil (CMF), and anthracycline-containing regimens. Metastatic breast cancer is unlikely to be cured by any method. Even with the most active therapies, complete remissions are uncommon, and only few of those in remission remain free of disease progression for a prolonged period 5). Because current approaches to the treatment of metastatic breast cancer are not associated with dramatic survival benefits, the focus of treatment is on palliation and QOL improvement. Successful palliative therapy requires the treating physician to reduce disease-related symptoms without 222

4 Breast Cancer Vol. 13 No. 2 April 2006 imposing excessive adverse events associated with treatment-related toxicity. Development of drugs to satisfy these severe demands is an indispensable challenge. A drug is generally considered to be efficacious in the metastatic setting if more than 20% of patients show a response in a phase II trial 6). Response rates of higher than 20% have been reported for several single agents including alkylating agents, anthracyclines and anthraquinones, antimetabolites, vinca alkyloids, and taxanes. The current first-line agent for most patients with hormone refractory metastatic diseases is either taxanes or anthracyclines. 5-fluorouracil (5-FU) was first introduced in 1957, and it has remained an essential part of the treatment for a wide range of solid tumors including gastrointestinal, head and neck, and breast cancers. In metastatic breast cancer, 5-FU has been widely used in combination with cyclophosphamide, methotrexate and anthracycline as CMF or CAF regimens, but these only a few cases in which it is used as monotherapy. Efficacy of 5-FU is markedly limited due to its rapid degradation into 5, 6-dihydro-5-fluorouracil (5-FUH2) via action of the cytosolic enzyme dihydropyrimidine dehydrogenase (DPD) in the liver or in tumors. It has been demonstrated that this enzyme deactivates more than 85% of the injected dose of 5-FU, and that the half-life (t1/2) of 5-FU is short (5 to 20 min) 7). Therefore, the efficacy of 5- FU appears to be highly dependent on the dosing schedule: frequent or prolonged infusions are superior to single-bolus administration. The toxicity profile of 5-FU is also schedule-dependent. For the bolus regimen, toxicities include myelosuppression, oral mucositis, and gastrointestinal toxicities such as diarrhea, stomatitis, nausea and vomiting, due to phosphorylation of 5-FU into 5- fluorouridine-5 -monophosphate (5-FUMP) by orotate phosphoribosyl transferase (OPRT) in the digestive tract 8). For the continuous regimen, toxic reactions include the hand-foot syndrome, which is observed in many cases, but less hematologic and gastrointestinal toxicities are observed. Treatment by continuous infusion thus presents advantages compared with treatment by bolus regimen with respect to both anti-tumor activity and toxicity. The development of permanent venous access devices and portable infusion pumps has allowed continuous infusion of 5-FU over prolonged periods. This method was designed to prolong the exposure of cells to the drug and thus enhance anti-tumor activity 9). However, portable infusion pumps are still not convenient, and indwelling catheters may induce complications such as venous thrombosis and infections around the catheter. For these reasons, one of the challenges of cancer research is developing new preparations of 5-FU that diminish or circumvent some of the disadvantages of current 5-FU preparations. The new preparations should reduce toxicity by circumventing certain routes of degradation, should enhance anti-tumor activity by reducing catabolism (use of DPD inhibitor) or by increasing anabolism, and should improve QOL of the patient 10). Capecitabine, UFT and S-1 have been developed as third generation compounds of fluoropyrimidine with the hope of permitting oral administration. S-1 (TS-1) consists of 1-(2-tetrahydrofuryl)-5- fluorouracil (FTO), a prodrug of 5-FU, and two other compounds, 5-chloro-2, 4-dihydroxypyrimidine (CDHP; gimestat) and potassium oxonate (OXO; otastat), in molar proportions of 1:0.4:1. In this combination formulation, FTO provides stable and prolonged liberation of 5-FU, which is as effective as continuous intravenous infusion of 5- FU. Neither CDHP nor OXO has any anti-tumor activity itself. They act solely as a modulator of 5- FU, and act on different metabolic pathways of 5- FU. CDHP is a potent and reversible inhibitor of DPD; thereby the plasma and tumor 5-FU levels are maintained above a minimal effective concentration for a long period 11). OXO is employed to limit the gastrointestinal toxicity of 5-FU. As described above, 5-FU related gastrointestinal toxicities are ascribed to the phosphorylation of 5-FU in the digestive tract by OPRT. OXO competitively inhibits OPRT after oral administration. The level of 5-FUMP is decreased in the gastrointestinal mucosa, and toxicity is reduced 12, 13). Phase I studies of S-1 have been conducted in Japan, Europe and the US, and Phase II trials in Japan. In a phase II trial of S-1 using 43 patients with advanced gastric cancer, RR is 44% (95% CI, %) and MST is 207 days 14). Grade 3 adverse reactions including decreased hemoglobin values were observed in 2 patients, leucopenia, neutropenia and diarrhea in one patient each. Grade 4 adverse reactions were not seen. In a phase II study of S-1 using 110 patients with metastatic breast cancer, the RR was 41.7% (95% CI, %), and MST is 872 days (95% CI, 572-1,110 days) 1). The incidence of toxicity ( grade 3) 223

5 Taira N, et al S-1 maintained complete response for 10 years in metastatic breast cancer was as follows: neutropenia in 9.1%, anemia in 0.9%, anorexia in 3.6%, stomatitis in 1.8%, nausea/ vomiting in 1.8%, diarrhea in 0.9%, and fatigue in 2.7%. There was no difference in toxicity between elderly (age >65) and younger patients. Hand-foot syndrome, which was observed relatively frequently in a phase II study of capecitabine, was not seen in this S-1 trial. The results of these phase II trials indicate that S-1 is well-tolerated and effective in metastatic breast cancer patients, even if they are elderly. In our case, two important characteristics of S- 1 were conspicuously shown. The first was the effectiveness of co-administration of FTO and CDHP. In this case, lung metastasis occurred during adjuvant treatment with HCFU, a prodrug of 5- FU. Nonetheless, S-1 showed remarkable antitumor activity. Prolongation of high 5-FU concentrations and sufficient efficacy might be achieved as results of DPD inhibition by CDHP in the liver or in tumors. S-1 could show activity in breast cancer patients pretreated with other fluoropyrimidines. The second was that the toxicity of S-1 was tolerable, and long-term administration approximately for 10 years was possible. The QOL of the patient could be maintained during the treatment period without serious adverse events. When treating metastatic breast cancer patients, further treatment is often withdrawn because of toxicity of the agent, instead of efficacy. Accordingly, S-1 might be very attractive because it showed low toxicity and tolerance to long-term oral treatment. Further clinical trials might be necessary to evaluate the efficacy and safety of S-1 in a larger number of patients, and to clarify the positioning of S- 1, in relation to anthracyclines or taxanes in the treatment of breast cancer patients. References 1) Saeki T, Takashima S, Sano M, Horikoshi N, Miura S, Shimizu S, Morimoto K, Kimura M, Aoyama H, Ota J, Noguchi S, Taguchi T: A phase II study of S-1 in patients with metastatic breast cancer- a Japanese trial by the S-1 Cooperative Study Group, Breast Cancer Working Group. Breast Cancer 11: , ) Early Breast Cancer Trialists Collaborative Group: Systemic treatment of early breast cancer by hormonal, cytotoxic or immune therapy: 133 randomised trials involving recurrences and deaths among women (part I). Lancet 339:1-15, ) Early Breast Cancer Trialists Collaborative Group: Effects of chemotherapy and hormonal therapy for early breast cancer on recurrence and 15-year survival: an overview of the randomised trials. Lancet 365: , ) Shinzaburo N, Hiroki K, Junichi U, Rikiya A, Shigeto M, Keizo S, Kohei A, Osahiko A: Postoperative adjuvant therapy with tamoxifen, tegafur plus uracil, or both in women with node-negative breast cancer: a pooled analysis of six randomized controlled trials. J Clin Oncol 23: , ) Greenberg PA, Hortobagyi GN, Smith TL, Ziegler LD, Frye DK, Buzdar AU: Long-term follow-up of patients with complete remission following combination chemotherapy for metastatic breast cancer. J Clin Oncol 14: , ) Simon R: Design and analysis of clinical trials. In: DeVita J,VT, Hellman S, Rosenberg S eds, Cancer: principles and practice of oncology, Lippincott Williams & Wilkins, New York, p521, ) Iyer L, Ratain MJ: 5-fluorouracil pharmacokinetics: causes for variability and strategies for modulation in cancer chemotherapy. Cancer Invest 17: , ) Meta analysis Group in Cancer: Toxicity of fluorouracil in patients with advanced colorectal cancer: effect of administration schedule and prognostic factor. J Clin Oncol 16: , ) Benson AB 3rd: Regional and systemic therapies for advanced colorectal carcinoma: randomized clinical trial results. Oncology (Huntingt) 12(Suppl 7):28-34, ) Martino MM, Martino R: Clinical studies of three oral prodrugs of 5-fluorouracil (Capecitabine, UFT, S-1): a review. Oncologist 7: , ) Hirata K, Horikoshi N, Aiba K, Okazaki M, Denno R, Sasaki K, Nakano Y, Ishizuka H, Yamada Y, Uno S, Taguchi T, Shirasaka T: Pharmacokinetic study of S- 1, a novel oral fluorouracil antitumor drug. Clin Cancer Res 5: , ) Shirasaka T, Shimamoto Y, Fukushima M: Inhibition by oxonic acid of gastrointestinal toxicity of 5-fluorouracil without loss of its antitumor activity in rats. Cancer Res 53: , ) Takechi T, Nakano K, Uchida J, Mita A, Toko K, Takeda S, Unemi N, Shirasaka T: Antitumor activity and low intestinal toxicity of S-1, a new formulation of oral tegafur, in experimental tumor models in rats. Cancer Chemother Pharmacol 39: , ) Sakata Y, Ohtsu A, Horikoshi N, Sugimachi K, Mitachi Y, Taguchi T: Late phase II study of novel oral fluoropyrimidine anticancer drug S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) in advanced gastric cancer patients. Eur J Cancer 34: ,

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