Oncologic Effect of Oral Fluorouracil in Hormone Receptor-Negative T1a Node-Negative Breast Cancer Patients

PURPOSE: As 5-fluorouracil (5-FU) has previously exhibited antitumor activity and few adverse effects in the treatment of breast cancer, we aimed to specifically assess the benefits of orally administered 5-FU in hormone receptor-negative small breast cancer. METHODS: We retrospectively identified patients with pT1aN0 and hormone receptor-negative breast cancer who underwent surgery between 1993 and 2008 at Asan Medical Center. Patients were divided into two cohorts based on adjuvant doxifluridine (Didox; Shin Poong Pharm. Co., Ltd.) administration, and the disease-free survival (DFS) and cancer-specific survival (CSS) was assessed for each cohort. RESULTS: Both cohorts had similar ages and tumor sizes. The DFS and CSS did not significantly differ between the groups (p=0.399 and p=0.126, respectively). When the cohorts were assessed according to human epidermal growth factor receptor 2 (HER2) status, doxifluridine significantly improved DFS among patients with T1aN0 and HER2-positive breast cancer (p=0.037). CONCLUSION: Doxifluridine did not yield a significant reduction in DFS events in hormone receptor-negative early breast cancer. However, a clear benefit was observed in hormone receptor-negative, HER2-positive T1aN0 breast cancer patients.

Reversible Leukoencephlaopathy Caused by Doxifluridine in a Patient with Gastric Cancer

Doxifluridine neurotoxicity is more rare than 5-FU neurotoxicity. We report a case of leukoencephalopathy caused by long-term use of doxifluridine and which was resolved after discontinuation. A 37-year-old woman who had been on doxifluridine for 4 months after gastrectomy presented with dysarthria. Diffusion-weighted MRI imaging revealed multifocal hyperintense lesions in subcortical areas. Her symptoms disappeared after discontinuing doxifluridine, and lesions on follow-up MRI were resolved. These findings suggest that doxifluridine is a plausible cause of reversible leukoencephalopathy.

Localized Scleroderma-like Reaction Induced by Doxifluridine / 대한피부과학회지

Exogenous factors, including environmental substances and drugs, are known to induce scleroderma-like reactions. Various scleroderma-like reactions induced by anti-cancer drugs have recently been reported. This is the first report that doxifluridine (Didox), an oral prodrug of the antineoplastic agent 5-fluorouracil (5-FU), induced a localized sclerderma-like reaction. A 51-year-old woman was referred to our clinic with multiple pearly, shiny patches on both her breasts, her pelvis and her back. After surgical excision and radiation therapy due to her right breast cancer, she took Didox for 7 months. A skin biopsy specimen revealed that the dermal collagen thickening extended even to the subcutaneous tissue. The routine laboratory tests were within the normal ranges and the tests for antinuclear antibody (ANA), anti SS-A antibody, anti SS-B antibody and anti U1-RNP antibody were all negative. After discontinuation of Didox, the lesions gradually improved. Based on these finding, we diagnosed this case as a localized scleroderma-like reaction induced by doxifluridine and we should pay attention to detect this adverse effect of the long term use of doxifluridine.

A Case of Doxifluridine-Induced Multiple Atypical Moles on the Palm and Sole of a Patient Taking Immunosuppressive Agents / 대한피부과학회지

Doxifluridine is a pyrimidine derivative and is activated to 5-fluorouracil by pyrimidine phosphorylase. Multiple acral hyperpigmented macules have been reported in patients treated with systemic 5-fluorouracil or some of its prodrugs. However, there have been no reports of this adverse event being induced by doxifluridine. Herein we present a 42-year-old woman with multiple pigmented lesions on the palm and sole after chemotherapy with oral doxifluridine.

A Case of Doxifluridine-Induced Ro/SSA-Positive Cutaneous Lupus Erythematosus / 대한피부과학회지

Anti-Ro/SSA antibody positive drug-induced lupus erythematosus is characterized by erythematous papules at the photodistributed area after drug intake, positive anti-Ro/SSA antibody tests and histopathologic features of lupus erythematosus. A 68-year-old man was referred to our clinic with multiple erythematous violacious plaques on the face of 2 months' duration. After surgical removal of stomach cancer, he had been taking doxifluridine for 10 months. A histopathologic study revealed findings consistent with lupus erythematosus and the anti-Ro/SSA antibody was positive on the serologic test. Based on these findings, we diagnosed this case as anti-Ro/SSA antibody positive drug-induced lupus erythematosus, and report it with review of the literature.

Prospective Randomized Trials Comparing Intravenous 5-Fluorouracil and Oral Doxifluridine as a Postoperative Adjuvant Treatment for Advanced Rectal Cancer

PURPOSE: Intravenous 5-Fluorouracil (5-FU) and oral doxifluridine were compared with respect to therapeutic efficacy, drug toxicity, and quality of life to clarify the efficiency of oral doxifluridine. METHODS: One hundred sixty-six (166) patients who underwent a curative resection for TNM stage II and III rectal cancer between Oct. 1997 and Feb. 1999 were randomized to receive intravenous 5-FU (450 mg/m2/day) or oral doxifluridine (700 mg/m2/day) in combination with leucovorin (20 mg/m2/day). 5-FU was infused intravenously 5 consecutive days per month for a total of 12 cycles (IV arm, N=74) in one group, and doxifluridine was given orally daily for 3 weeks with a rest of 1 week for a total of 12 cycles (Oral arm, N=92). Drug toxicity and quality of life were observed. Quality of life was scored according to twenty-two daily activity items (good,>71, fair,530.05). Mean number of chemotherapy cycles was 6.5+/-3.7 (IV arm) vs 7.2+/-4.3 (Oral arm). The recurrence rate was 9/74 (12.1%) in IV arm and 6/92 (6.5%) in oral arm (P=0.937). Local recurrence was 2/74 (stage III; 2.7%) in IV arm and 1/92 (stage II; 1.1%) in oral arm. Systemic recurrence was 7/74 (Stage III; 9.4%) in IV arm and 5/92 (Stage III; 5.4%) in oral arm. Toxicity pro-files are as follows: Leukopenia (30/74, 17/92) and alopecia (21/74, 13/92) were more common in IV arm than in oral arm, and the difference was statistically significant. Diarrhea was more common in oral arm. The quality of life score was better at 1 month (19.5%, 49%) and at 2 months (47%, 72%) in the oral arm group (<0.05). CONCLUSION: Oral Doxifluridine with leucovorin as a postoperative adjuvant therapy shows a therapeutic efficacy comparable to the intravenous 5-FU regimen and has a high quality of life. The oral regimen also can be safely given with an appropriate toxicity and tolerability.

Prospective Randomized Trial Comparing Intravenous 5 Fluorouracil and Oral Doxifluridine as Preoperative Concurrent Chemoradiation for Locally Advanced Rectal Cancer

PURPOSE: Preoperative radiation treatment with concomittant intravenous infusion of 5-fluorouracil has been known to be effective in shrinking and downstaging the tumor. Treatment with Doxifluridine (synthetic 5-deoxynucleoside derivative) medication prolongs drug exposure to tumor tissue, so it can be considered synergistic to concurrent radiotherapy. Intravenous 5-FU and oral Doxifluridine were compared with respect to tumor response, toxicity, and quality of life of patients. METHODS: Twenty eight patients with rectal cancer, staged as over T3N1 or T4 by transrectal ultrasonography between July 1997 and December 1998 were included. Intravenous 5-FU (450 mg/m2/day) and leucovorin (20 mg/m2) was given for five consecutive days during first and fifth weeks of irradiation therapy (50.4 Gy) (N=14). Oral Doxifluridine (700 mg/m2/day) and leucovorin (20 mg/m2) was given daily during radiation treatment (N=14). Quality of life was scored according to twenty two activity items (good: >77, fair: >58, poor: <57). Surgical resection was performed four weeks after completion of concurrent chemoradiation treatment. Tumor response was classified as CR (Complete Response), PR (Partial Response: 50% diminution of tumor volume or downstaging), or NR (No Response). RESULTS: Tumor response was CR: 3/14 (21.4%), PR: 7/14 (50%) and NR: 4/14 (28.6%) in IV arm versus CR: 2/14 (14.2%), PR: 6/14 (42.9%) and NR: 6/14 (42.9%) in oral arm (p=0.16, 0.23, 0.24, respectively). Quality of life was poor (36.4% vs 33.3%), fair and good (63.6% vs 66.7%, respectively) between IV arm and oral arm. Systemic recurrence during follow up periods was 1/14 (7.1%) in IV arm and 2/14 (14.3%) in oral arm, respectively (p=0.307). One local recurrence was observed in oral arm. Hematologic toxicity was 3/14 (21.4%) in IV arm versus 4/14 (28.5%) in oral arm, respectively. Gastrointestinal toxicity was 2/14 (14.3%) versus 5/14 (35.7%) and stomatitis was observed in IV arm (1/14, 7.1%) CONCLUSION: Oral doxifluridine based chemotherapy shows a comparable tumor response and oncologic results, but there was no benefits as far as quality of life and toxicity were concerned.