A case of paclitaxel and trastuzumab-resistant recurrent breast cancer with liver metastasis responding to S-1

We experienced a case of paclitaxel- and trastuzumab-resistant recurrent breast cancer with liver metastases showing significant improvement by S-1. A 76-year-old woman was diagnosed with left breast cancer(T2N1M0, Stage II B). She received total mastectomy and CEF(cyclophosphamide 500 mg/m(2), epirubicin 60 mg/m(2), 5-FU 750 mg/m(2))as adjuvant chemotherapy in March 2004. But twelve months later, she was referred to our clinic for management of lung and left supraclavicular lymphnode metastases. Then weekly paclitaxel(80 mg/m(2))and trastuzumab were started. After 2 cycles of weekly paclitaxel and trastuzumab treatment, lung and lymphnode metastases were reduced and the patient showed a clinical response(CR), so she was treated by trastuzumab only. But seven months later, she was diagnosed as a recurrence of liver metastases. She was treated by combined paclitaxel and trastuzumab again, but liver metastases and tumor marker were progressive. S-1 was administered orally 100 mg/day every day for 4 weeks, followed by a 2-week rest interval as 1 cycle, and trastuzumab was injected at 2 mg/kg/week for every weeks. After 2 courses of the treatment, the level of tumor marker and tumor size of liver metastases were reduced. Only rash(grade 1)was observed during treatment. The treatment of S-1 is thought to be effective for taxane-resistant recurrent breast cancer.     

A novel combined chemotherapy using TS-1 and low-dose cisplatin against liver metastasis of gastric cancer

We used a novel combination chemotherapy of TS-1 and low-dose cisplatin (CDDP) with 4 gastric cancer patients with liver metastases (one far advanced and 3 recurrent patients). TS-1 was administered at 80 mg-120 mg/body/day, twice daily for 3 weeks followed by a 2-week interval as one cycle, and CDDP was administered at 6 mg/m2/day div, for 5 days followed by a 2-day interval (1 cycle for an inpatient) or at 6 mg/m2/day div, at 5 times for 2-3 weeks (1 cycle for an outpatient). Efficacy and toxicity were evaluated after 3-6 cycles of the regimen, as long as the patients tolerated the regimen without severe side effects. This regimen resulted in 1 complete response, 2 partial responses and 1 progressive disease, showing a 75% efficacy rate. One patient experienced grade 2 nausea from this regimen, which was ameliorated by means of prolonging the interval of CDDP-administration. Thus, the regimen is useful to maintain patients' quality of life without severe adverse effects, and has a high efficacy in gastric cancer patients with liver metastases.     

Phase 2, Multicenter,Single-Arm Study of Eribulin Mesylate With Trastuzumab as First-Line Therapy for Locally Recurrent or Metastatic HER2-Positive Breast Cancer

BackgroundThe aim of this study was to assess efficacy and safety of eribulin with trastuzumab as first-line therapy for locally recurrent or metastatic HER2+ breast cancer.Patients and MethodsIn this multicenter, phase II, single-arm study, patients with recurrent or metastatic HER2+ breast cancer received eribulin mesylate at 1.4 mg/m² intravenously (I.V.) on days 1 and 8 of each 21-day cycle with an initial trastuzumab dose of 8 mg/kg I.V. on day 1, followed by 6 mg/kg of trastuzumab on day 1 of each subsequent cycle. Tumor assessments were conducted every 6 weeks for the first 6 cycles and every 12 weeks thereafter. The primary end point was ORR, and secondary end points included PFS, TTR, DOR, and safety.ResultsFifty-two patients were enrolled. Fifty-one patients (98.1%) had metastatic disease, 25 (48.1%) with liver metastases, 24 (46.2%) with lung metastases, and 19 (36.5%) with bone metastases. Patients received a median of 10.0 cycles of eribulin and 11.0 cycles of trastuzumab. The ORR was 71.2% (n = 37) with median TTR of 1.3 months, DOR of 11.1 months, and PFS of 11.6 months. The most common Grade 3/4 treatment-emergent adverse events were neutropenia in 20 (38.5%) patients, peripheral neuropathy in 14 (26.9%; all Grade 3) patients, fatigue in 4 (7.7%) patients, and febrile neutropenia in 4 (7.7%) patients.ConclusionsBecause of the high ORR, prolonged median PFS, and acceptable safety profile, combination eribulin/trastuzumab is an acceptable treatment option for locally recurrent or metastatic HER2+ breast cancer.     

A case of effective treatment of oral TS-1 and intravenous MMC administration for multiple metastases of gastric cancer

A 49-year old man underwent distal gastrectomy (D3) for circumferential type 3 cancer at the gastric antrum and cholecystectomy in September 2002. During the surgery, multiple metastases were observed predominantly in the left lobe of the liver, and lateral segmentectomy was performed as non-curative (curability-C) resection leaving the small metastases in the right lobe of the liver. Based on the results of chemo-sensitivity tests (5-FU 15.0%, CDDP 34.0%, MMC 35.3%, TXT 0.0%), we started to administer TS-1 (100 mg/day for 4 weeks followed by a 2-week rest interval) and MMC (10 mg/body on day 1). Due to leukocytopenia, the regimen was changed to TS-1 (100 mg/day for 4 weeks followed by a 2-week rest interval) and MMC (4 mg/body every other week [day 1, 14]) from the second course. Levels of tumor markers dropped and liver metastatic lesions remarkably decreased in size by CT after the third course. In conclusion, a combination of TS-1/MMC may be regarded as one option for postoperative adjuvant chemotherapy for outpatients.     

Combination chemotherapy with oral TS-1 and low-dose CPT-11 by hepatic arterial infusion for multiple hepatic metastases from colon cancer--a case report

Combined chemotherapy consisting of oral TS-1 and low-dose CPT-11 by hepatic arterial infusion is suggested to be a new effective treatment for multiple liver metastases from colorectal cancer. A 53-year-old man was diagnosed with multiple hepatic metastases from advanced colon cancer (Stage IV). The patient underwent partial resection of the colon and catheter insertion into hepatic artery for arterial infusion in November 2003. He was treated with postoperative combination chemotherapy consisting of UFT and low-dose CPT-11. UFT was administered orally at 400 mg/body/day everyday and CPT-11 was injected at 40 mg/body/week for 6 weeks, followed by a 2 weeks rest interval as 1 cycle. In spite of the reduction of metastatic liver tumors after 2 cycles of the chemotherapy, a metastatic pleural tumor appeared. Therefore, we judged the effect of the chemotherapy to be a progressive disease and changed UFT in the regimen to TS-1. TS-1 was administered orally at 80 mg/body/day under a 2-weeks-on and 1-week-off regimen for 3 times. CPT-11 was injected at 40 mg/body/week for 6 weeks, followed by a 3 weeks rest interval as 1 cycle. A stable disease was maintained for 3 months. Outpatient care was possible because no severe events were observed. Tumors showed a reduction rate of 37.4% after the combination therapy. The patient survived for 285 days after the operation.     

替吉奥单药治疗晚期胃癌的近期疗效及安全性评价

目的探讨替吉奥单药或联合最佳支持治疗用于晚期胃癌治疗的疗效与不良反应。方法对符合入组条件的胃癌患者采用替吉奥每日80mg/m2,分二次在早晚饭后半小时用水吞服。连续2周停1周,3周重复。结果 48例患者共接受195周期替吉奥单药化疗,完全缓解（CR）0例,部分缓解（PR）21例（43.8%）,稳定（SD）24例（50.0%）,治疗总有效率（RR）43.8%。主要不良反应为消化道反应,骨髓抑制。结论替吉奥单药治疗晚期胃癌疗效较好,不良反应轻而且安全,是治疗晚期胃癌,特别是年龄较大、一般状态较差的患者的安全有效的治疗方案。     

Weekly administration of paclitaxel might be beneficial against TS-1-resistant recurrent gastric cancer--a case report

At one year after postoperative adjuvant therapy consisting of TS-1, UFT, and PSK, lymph-node metastasis and recurrent suprarenal metastasis were confirmed in a patient with Stage IV gastric cancer. Despite TS-1 therapy (120 mg/body, 4 consecutive weeks, 2-week break), the therapeutic effect remained PR, and the severity of adverse reactions, such as skin symptoms, leukopenia, and diarrhea, ranged from grade 1 to 3. Although this therapy was continued intermittently, the therapeutic effect worsened to PD and, as a result, the therapy was discontinued. Next, in accordance with the treatment of recurrent and advanced breast cancer, weekly paclitaxel (PTX 80 mg/m2, 3 consecutive weeks, 1-week break) administration was performed on an outpatient basis. CR was achieved after 4 cycles. In addition, no adverse reactions were seen. Therefore, the weekly administration of PTX for the treatment of recurrent gastric cancer resistant to 5-FU anticancer agents is extremely useful, as the antitumor effect of this therapy was great, no adverse reactions were seen, and it can be performed on an outpatient basis.     

A case of recurrent gastric cancer with peritoneal dissemination successfully treated with DJ stents against bilateral hydronephrosis and chemotherapy

A 69-year-old female patient underwent total gastrectomy with a D2 lymph node dissection. Her final findings were of pT2, pN0, sP0, sH0, sM0 and Stage IB. After thirty-five months from the operation, peritoneal recurrence with ascites, bilateral hydronephrosis and stenosis of colon was found. TS-1 (80 mg/day/body) was administered for four weeks followed by a 2-week rest after DJ stents were inserted into bilateral ureters. At the end of two courses of TS-1, ascites disappeared and the decrease of tumor marker was observed. During the seventh course, symptoms such as abdominal fullness and ascites became worse. She underwent a weekly administration of paclitaxel (90 mg/body) as a second-line chemotherapy. This regimen was continued for three weeks followed by a 1-week rest. After four courses of paclitaxel, ascites disappeared and the tumor marker was gradually reduced. However, multiple bone metastases were found during the eighth course, and she died about two years after the recurrence. The toxic events were mucositis (grade 1) in TS-1, and alopecia (grade 2) and leukopenia (grade 1) in paclitaxel. No major adverse effects were observed. Although the prognosis of recurrent gastric cancer with peritoneal dissemination was extremely poor, this case might suggest a possibility that intensive therapies are useful in maintaining the quality of life and improving survival.     

Successful treatment of gastric cancer accompanied by multiple liver metastases with TS-1 followed by curative gastrectomy affiliation

Despite the improvement in the operative results for patients with gastric cancer, the prognosis of those with liver metastasis remains dismal. Multimodal therapy has attracted considerable attention as a breakthrough in the strategy for treating cases of highly advanced gastric cancer. We report the case of a 62-year-old female with gastric cancer accompanied by multiple liver metastases successfully treated by TS-1, a novel oral fluoropyrimidine derivative. One treatment course consisted of 4 weeks of TS-1 administration (100 mg daily) followed by a 2-week break. After 3 courses of treatment, an abdominal CT scan showed no evidence of liver metastases and gastroscopy revealed that the primary gastric lesion was reduced. Grade 1 toxicity (nausea and diarrhea) was seen but 6 days rest improved the condition. Distal gastrectomy was subsequently performed without any finding of residual tumor. TS-1 may have a promising role in neoadjuvant chemotherapy for gastric cancer.     

A case of osteonecrosis of the jaw in a breast cancer patient with bone metastases receiving long-term treatment with bisphosphonates

Bisphosphonates (BPs) are often used for the treatment of several diseases such as osteoporosis, cancer-associated hypercalcemia, and osteolytic bone metastasis. Recently, there have been reports of osteonecrosis of the jaw (ONJ) in cancer patients whose treatment regimens include BPs. In this case report, we describe complications and treatment of ONJ in a breast cancer patient with bone metastases who received long-term treatment with BPs. A 70-year-old woman underwent modified radical mastectomy on her left breast cancer and received oral 5-fluorouracil derivatives for 2 years in another hospital. Eleven years after the surgery, she came to our hospital complaining of spinalgia and was diagnosed with recurrent breast cancer with multiple metastases to the stomach, liver, multiple lymph nodes, and spine. After surgery for spine metastases, she was given a combination therapy of trastuzumab (initial bolus: 170 mg/body, followed by two or more cycles of 85 mg/body) every week, docetaxel (100 mg/body) every 3 weeks, and BPs (90 mg/body) every 4 weeks. About 1 year and 4 months later, she complained of pain in her right maxilla; biopsy revealed ONJ. Medical oncologists need to recognize ONJ as a serious side effect of BP treatment; dentists and oral and maxillofacial surgeons need to thoroughly consult patients regarding the administration of BPs and have them make an informed consent.     

Feasibility and therapeutic efficacy of weekly 1-h low-dose paclitaxel infusion for relapsed breast cancer

The therapeutic efficacy of weekly paclitaxel infusion for relapsed breast cancer patients is not known. We assessed safety, feasibility, and therapeutic efficacy in a pilot study of weekly 1-h low-dose paclitaxel infusion for relapsed breast cancer in an outpatient clinic. Eighteen patients with relapsed breast cancer who had received prior chemotherapy regimens, including anthracyclines, mitomycin, and 5-fluorouracil beyond a second line of treatment were enrolled into the study. The dose of paclitaxel was between 40 mg/m(2) and 80 mg/m(2) per week in a 1-h infusion, and a treatment cycle was 4 weeks until there was no evidence of progressive disease. When a dose of 80 mg/m(2) was administered, the treatment cycle was weekly infusion three times with a 1-week interval per 4-week cycle. The mean treatment period was 5.5 months and the maximal length of administration was 8 months. The overall response rate was 44.4%, including 2 cases of complete response and 6 cases of partial response. Tumor response was observed in 3 of 7 cases of lung metastases (42.8%), 6 of 12 cases of soft tissue metastases (50.0%), and 1 of 3 cases of liver metastases (33.3%), whereas 8 cases with bone metastases did not respond. The mean time to response was 1.8 months and the mean response duration was 4.3 months. The dose between 31.5 mg/m(2)/wk and 79.7 mg/m(2)/wk was not associated with tumor response. Toxicities associated with weekly 1-h low-dose paclitaxel infusion were tolerable, and most were less than grade 2, including alopecia (100%), neutropenia (88.8%), flushing (66.6%), face edema (61.1%), numbness (55.5%), and myalgia (38.8%). There was 1 case of grade 3 neutropenia. Weekly 1-h low-dose paclitaxel might be a therapeutically effective, safe infusion and feasible as a salvage chemotherapy for relapsed breast cancer patients following failure of prior chemotherapy.     

Clinical efficacy of TS-1 combined with cisplatin for advanced cardiac gastric cancer with multiple liver metastases--two case reports

Case 1: A 62-year-old man was introduced to our hospital for Type 1 cardiac gastric cancer. On the abdominal CT, there was evidence of multiple liver metastases. The patient was treated with daily oral administration of TS-1 (120 mg/day) for 3 weeks followed by 2 weeks' rest and infusion of CDDP (60 mg/m2) on day 8 as 1 course. After completion of 1 course, partial response in the primary tumor, and complete responses in the liver and lymph node metastases had been assessed, although the primary tumor increased during the 2 months' rest after 4 courses. Case 2: A 67-year-old man was hospitalized for Type 3 cardiac gastric cancer with multiple liver and lymph node metastases. A combination of TS-1 (100 mg/day), and CDDP (60 mg/m2), and TS-1 (80-50 mg/ day) was used. After 2 courses of TS-1/CDDP and 4 courses of TS-1, the primary tumor decreased significantly in size, and complete responses in the liver and lymph node metastases had been assessed, although the primary tumor, liver and lymph node metastases increased after 6 courses of TS-1. The two cases under study suggest that the combination systemic chemotherapy of TS-1 and CDDP is an effective treatment for advanced gastric cancer with multiple liver metastases in terms of its antitumor effect and QOL of the patients.     

A partial response to combined TS-1 and docetaxel chemotherapy enabling a curative resection after the failure of combined TS-1 and CDDP chemotherapy in a patient with unresectable gastric cancer

A 60-year-old man visited our hospital complaining of epigastric pain. Gastrofiberscopy revealed an advanced gastric cancer located on the anterior wall of the antrum. Abdominal computed tomography (CT) revealed metastases to the paraaortic lymph nodes. The patient subsequently underwent combined chemotherapy consisting of TS-1 and low-dose CDDP for the treatment of unresectable gastric cancer. No reductions in the paraaortic lymph node metastases were noted after one cycle. The patient was then treated with TS-1 combined with docetaxel as a second-line chemotherapy. TS-1 (80 mg/m2) was orally administered for 2 weeks followed by a 2 week interval, while docetaxel (25 mg/m2) was simultaneously administered weekly (days 1, 8, and 15). One cycle of chemotherapy was 28 days. An abdominal CT revealed a partial response after 3 cycles. The patient experienced grade 2 leukocytopenia and grade 3 neutropenia. We decided that the patient could undergo a curative resection, and a distal gastrectomy with D2+para-aortic LN dissection was performed. The pathological efficacy was Grade 2. The patient is presently alive with no sign of recurrence after 20 months. Combined TS-1 and docetaxel chemotherapy is a promising second-line regimen for the treatment of unresectable gastric cancer, after treatment with TS 1 combined with CDDP has failed.     

A case responding to weekly paclitaxel therapy as second-line chemotherapy for gastric cancer previously treated with TS-1

A 58-year-old male patient with the recurrence of para-aortic lymphnodes after TS-1 treatment was treated by a weekly infusion of paclitaxel as second-line chemotherapy. Paclitaxel was administered at a weekly dose of 70 mg/m2/day for three weeks followed by a one week interval. After 2 courses, the tumor was reduced, and the reduction was judged as PR. Moreover, after 5 courses, the tumor was more remarkably reduced and the reduction was judged as CR. The grade 2 leukopenia, neutropenia, and grade 1 alopecia were observed as adverse events. Recently, we treated 11 patients of advanced or recurrent gastric cancers with measurable lesions, using the weekly paclitaxel therapy after TS-1 treatment. The response rate was 36.4%. The median duration of PR was 130 days. Therefore, a weekly paclitaxel regimen was considered to be one of the promising regimens for advanced or recurrent gastric cancer as the second-line chemotherapy after TS-1 treatment.     

A case of advanced colon cancer with metastases to both para-aortic lymph nodes and cervical vertebrae effectively treated by TS-1 therapy

The patient was a 68-year-old woman who had cecal cancer with para-aortic lymph node metastases. Ileocecal resection was performed palliatively. Since metastasis to cervical vertebrae was detected after the operation, she received radiation therapy of 14 Gy to improve neck pain. Chemotherapy with TS-1 (80 mg/day) was started on an outpatient basis (4 weeks administration followed by a 2-week drug-free period). After 4 courses of this chemotherapy, metastases to both para-aortic lymph nodes and cervical vertebrae were remarkably reduced on CT and PET. Throughout the period of treatment, there was no adverse effect and this treatment has been maintained. In conclusion, this case seems significant from the viewpoint of achieving a partial response to TS-1 and maintaining a high quality of life. Moreover,we identified the presence of TS and DPD using an immunohistochemical staining technique. The primary tumor was positive for DPD stain test and negative for TS stain test. It was suggested that this cancer especially would respond to TS-1 chemotherapy.     

A case of gastric cancer with multiple liver metastases responding to TS-1

We report the case of a 58-year-old male with Stage IV gastric cancer accompanied by multiple liver metastases, which responded to chemotherapy using TS-1. The patient was treated with daily oral administration of 120 mg TS-1 for 4 weeks followed by 2 weeks rest as 1 cycle. After 4 cycles, most of the liver metastases had disappeared and serum CEA level was reduced from 140 to 53.9. The patient received chemotherapy at our outpatient clinic for 9 months during which time there was no regrowth after the first treatment. The current case suggests that TS-1 may have a potent therapeutic efficacy in cases of advanced gastric cancer.     

A case of advanced gastric cancer with bone metastases and DIC responding to oral administration of TS-1

The patient was a 71-year-old man whose chief complaints were staggering and fatigue. As a result of various examinations, he was diagnosed with advanced gastric cancer, Borrmann 3, with disseminated intravascular coagulation (DIC) and bone metastases. The DIC was treated with oral administration of TS-1 (120 mg/day). Furthermore, both the primary gastric tumor and metastatic bone lesions were reduced in size by the treatment with TS-1. TS-1 appears to be an effective therapeutic agent for advanced gastric cancer with DIC or bone metastases.     

A patient with multiple bone metastases from gastric cancer after an 8-year disease-free interval following gastrectomy

We present a patient with multiple bone metastases who was treated successfully using only TS-1. Metastasis was diagnosed 8 years after distal gastrectomy for early gastric cancer in a woman now 61 years old. Surgery was performed on February 13, 1995. The primary tumor was located in the midportion of the gastric body, and had invaded the submucosa with metastasis to lymph nodes in the area of the lesser curvature and the left gastric artery. She was discharged from our hospital 41 days after surgery. After the 8 years of follow-up, elevation of alkaline phosphatase (ALP: 1,029 IU/l) was noted. Bone scintigraphy disclosed scattered areas of uptake in systemic bones. The biopsy specimen from the pubic bone contained metastatic adenocarcinoma, and the bone lesions were diagnosed as multiple bone metastases from gastric cancer. Chemotherapy was started with oral administration of TS-1 alone at 80 mg/day for 2 weeks, followed by 2 weeks of rest. The patient did not experience any side effects, and treatment was repeated on an outpatient basis. At 4 month after initiation of therapy, decreases in ALP and number of foci of abnormal bone uptake in scintigrams were noted. She has survived for an additional 16 months after starting TS-1, without major complications.     

Two cases of recurrent gastric cancer treated by combined chemotherapy of TS-1 and low-dose cis-platinum

We report 2 patients with recurrent gastric cancer treated by combined chemotherapy of TS-1 and low-dose cis-platinum (TS-1/LCDDP). Who both obtained long-term survival while maintaining good QOL. Case 1: A 60-year-old man underwent total gastrectomy for gastric cancer (pT3, pN2, Stage III B). Three months after surgery, multiple liver metastases were identified, for which TS-1/LCDDP therapy (TS-1 100 mg/body/day, CDDP 10 mg/body/week; 1 course for 4 weeks) was started without hospitalization. After CR was obtained after 4 courses, an additional 4 courses were carried out. At present, 1 year and 11 months have passed since the initial treatment, and CR has been maintained. Regarding adverse events, only grade-1 pigmentation was observed. Case 2: A 65-year-old man with gastric cancer (pT3, pN1, Stage III A) underwent distal gastrectomy. One year after surgery, CT showed both multiple liver and pulmonary metastases. Twelve courses of TS-1/LCDDP therapy have been carried out for 2 years and 4 months. Therapeutic effect was NC, but the patient was able to tolerate the treatments as an outpatient without any subjective symptoms. Leukopenia (grade 2), pigmentation, stomatitis and nausea (grade 1) were observed. Both patients received TS-1/LCDDP therapy as outpatients with good QOL and performance status (0). Recently, chemotherapy for recurrent cancer has been focusing on long-term survival and maintenance of QOL, instead of tumor shrinkage. These results suggest that TS-1/LCDDP treatment is useful as a first-line chemotherapy for patients with recurrent gastric cancer.     

A new therapeutic approach to advanced and recurrent gastric cancer by TS-1]

In the present study, we demonstrate the treatment results of TS-1 on 22 gastric carcinoma patients (15 far advanced and 7 recurrent patients) from June 1999 to December 2000. TS-1 was administered at 75 mg/m2/day, twice daily per body for 28 days followed by a 14-day interval (1 cycle). Successful treatment was obtained in from 1 to 11 cycles, and we obtained 9 (47.4%) partial responses (PR), 7 stable disease (NC) and progressive disease (PD) among 19 evaluable patients. PR was obtained in 7 (58.3%) out of 12 primary lesions of the stomach. We also obtained 1 CR of liver metastasis and 4 PR of 9 distant lymph node metastases (44.4%). Moreover, malignant ascites disappeared in 4 (57.1%) out of 7 cases and PR was obtained in 3 (50%) out of 6 measurable cases of peritoneal disease. In addition, two patients had hydronephrosis which improved after 1 cycle of TS-1 treatment. The adverse effects observed were grade 3 bone marrow suppression in three cases, severe diarrhea in one case, one case of liver dysfunction and a few cases of nausea and vomiting. These results indicate that the oral tegafur compound, TS-1, is a new therapeutic tools for advanced and recurrent gastric carcinomas, especially peritoneal disease.