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Objective: Netupitant is a novel, selective neurokinin-1 receptor antagonist used for prevention of chemotherapy-induced nausea and vomiting, a distressing side effect of chemotherapy. This double-blind, randomized, Phase II study investigated the dose-response of oral netupitant in Japanese patients receiving highly emetogenic chemotherapy., Methods: Chemotherapy-naïve patients were randomized (1:1:1) to a single oral netupitant 30-, 100- or 300-mg dose before chemotherapy initiation. Patients received concomitant palonosetron (0.75 mg intravenously [i.v.] Day 1) and dexamethasone (9.9 mg i.v. Day 1, 8 mg orally Days 2-4)., Results: Overall, 402 patients (30 mg: 134; 100 mg: 135; 300 mg: 133) were treated and evaluable for efficacy and safety. The primary endpoint of overall (0-120 h after chemotherapy administration) complete response (CR) rate (no emesis, no rescue medication) was 64.2%, 60.0% and 54.9% in the 30-, 100- and 300-mg arms, respectively, without statistical significance for dose-response. The safety profile of netupitant was comparable in the three arms. The plasma concentrations of netupitant and its metabolites increased with the dose increase from 30 mg to 300 mg., Conclusions: No dose-response relationship of netupitant in terms of overall CR rate was observed in this study. Netupitant was well tolerated at all doses without clinically harmful safety signals observed., Clinical Trial Registration: JapicCTI-142 483.

Background: We investigate rates of pathologic complete response (pCR) and tumor expression of ER, PgR, HER2 discordance after neoadjuvant chemotherapy using Japanese breast cancer registry data., Patients and Methods: Records of more than 300,000 breast cancer cases treated at 800 hospitals from 2004 to 2013 were retrieved from the breast cancer registry. After data cleanup, we included 21,755 patients who received neoadjuvant chemotherapy and had no distant metastases. pCR was defined as no invasive tumor in the breast detected during surgery after neoadjuvant chemotherapy. HER2 overexpression was determined immunohistochemically and/or using fluorescence in situ hybridization., Results: pCR was achieved in 5.7% of luminal tumors (n = 8730), 24.6% of HER2-positive tumors (n = 4403), and 18.9% of triple-negative tumors (n = 3660). Among HER2-positive tumors, pCR was achieved in 31.6% of ER-negative tumors (n = 2252), 17.0% of ER-positive ones (n = 2132), 31.4% of patients who received trastuzumab as neoadjuvant chemotherapy (n = 2437), and 16.2% of patients who did not receive trastuzumab (n = 1966). Of the 2811 patients who were HER2-positive before treatment, 601 (21.4%) had HER2-negative tumors after neoadjuvant chemotherapy, whereas 340 (3.4%) of the 9947 patients with HER2-negative tumors before treatment had HER2-positive tumors afterward. Of the 10,973 patients with ER-positive tumors before treatment, 499 (4.6%) had ER-negative tumors after neoadjuvant chemotherapy, whereas 519 (9.3%) of the 5607 patients who were ER-negative before treatment had ER-positive tumors afterward., Conclusion: We confirmed that loss of HER2-positive status can occur after neoadjuvant treatment in patients with primary HER2-positive breast cancer. We also confirmed that in practice, differences in pCR rates between breast cancer subtypes are the same as in clinical trials. Our data strongly support the need for retest ER, PgR, HER2 of surgical sample after neoadjuvant therapy in order to accurately determine appropriate use of targeted therapy., (© The Author 2015. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Background: Accurate evaluation of renal function is required before cancer chemotherapy. Various kinds of formula have been developed for estimating creatinine clearance (Ccr) or glomerular filtration rate (GFR) conveniently. We retrospectively examined the reliability of the GFR estimating formula using the renal function data in cancer chemotherapy., Methods: Clinical data of 12 patients with urogenital cancer from 1998 to 2013 in Saga University Hospital were reviewed. Patients were treated with 6-21 (median 10.5) courses of chemotherapy and those patients underwent 9-29 (median 14.5) times of 24hrCcr tests before and during chemotherapy. We compared estimated GFR (eGFR) with 24hrCcr. In addition, we developed a novel method to estimate the Ccr using the patient-inherent 24hrCcr/eGFR ratio, which is calculated from initial 3 or 4 determinations of 24hrCcr and the corresponding eGFR. Those estimated Ccrs were also compared with 24hrCcr., Results: The dissociation between 24hrCcr and eGFR was not constant, and a large dissociation was observed in some cases. The newly devised estimated Ccr demonstrated less dissociation from 24hrCcr compared with eGFR., Conclusions: The eGFR formula is not adequate for the clinical use in cancer chemotherapy. The absolute value of eGFR is not reliable, but clinical use of eGFR as relative value seems to be acceptable. To avoid troublesome 24hrCcr measurement in long-term cancer chemotherapy, eGFR formula can be used for estimating Ccr in combination with the specific inherent 24hrCcr/eGFR ratio, which is obtained from 3 or 4 times of actual 24hrCcr measurements.

Background: Bisphosphonates have been used successfully in the treatment of hypercalcemia and to reduce skeletal complications of bone metastasis, but have not been shown to prevent bone metastasis or to prolong survival time in metastatic breast cancer patients. The aim of this study was to determine whether the progression-free survival (PFS) and overall survival (OS) of patients with bone-only breast cancer metastasis differed based on whether patients received zoledronic acid, pamidronate, or no bisphosphonate upon diagnosis of their metastases., Patients and Methods: We retrospectively identified 314 patients diagnosed with bone-only metastasis at the time of initial staging or who developed bone metastasis as the first recurrence site during follow-up from January 1, 1997 to December 31, 2008, at The MD Anderson Cancer Center. Univariate and multivariate Cox hazards models were used to assess the effects of each treatment on PFS and OS., Results: Patients who had more than 1 bone metastasis and Eastern Cooperative Oncology Group (ECOG) performance status of 2 and 3 were more likely to receive zoledronic acid in this analysis. Compared with no bisphosphonate use, the use of zoledronic acid was not significantly associated with longer PFS (hazard ratio [HR] = 0.72, P = .058 in univariate analysis, and HR = 0.80, P = .235 in multivariate analysis) nor with longer OS (HR = 1.04, P = .863 in univariate analysis and HR = 1.34, P = .192 in multivariate analysis)., Conclusion: Our study demonstrates that for patients with bone-only metastases, zoledronic acid did not prolong PFS or OS. In patients with bone-only metastasis, we could not demonstrate antitumor effects of zoledronic acid., (Copyright © 2011 American Cancer Society.)

Background: While the benefit of passive immunotherapy is commonly accepted, active immunization may have advantages for the patient's quality of life. We identified a new epitope of Mab CH401 against Her-2/neu extracellular domain (N: 167-175), and evaluated the effect of active immunization of the 20mer peptide containing the epitope (CH401 peptide)., Materials and Methods: Epitope-mapping was performed using ELISA with Her-2/neu-related multiple antigen peptides (MAP). BALB/c mice were transplanted with Her-2/neu-expressing lymphoma cell line and immunized with the peptides. For monitoring the condition, ELISA and flow cytometry was performed., Results: CH401 peptide induced Her-2/neu-specific IgG antibody. Tumor growth in immunized mice was suppressed and tumor-infiltrating lymphocytes comprised more CD8(+) T-cells, which secreted larger amounts of interleukin-2 after the peptide re-stimulation., Conclusion: The new Her-2/neu peptide contained epitopes for CD4(+) and CD8(+) T-cells, which contributes to the suppressive effect on Her-2/neu-expressing tumor cell growth.

Objective: The purpose of this study was to assess the safety of S-1 in Japanese in inoperable or recurrent breast cancer patients., Methods: A prospective post-marketing surveillance was performed at 313 sites in Japan in patients with inoperable or recurrent breast cancer treated with S-1. We examined 1361 patients between January 2006 and December 2007 with regard to the incidence of adverse drug reactions graded by the Common Terminology Criteria for Adverse Events (CTCAE), version 3.0., Results: At least one adverse drug reaction was encountered by 858 patients, with an overall incidence of 63.0% (858/1361). The incidence of Grade 3 or higher adverse drug reactions in a descending order was 14.7% (200/1361). In this study, the most common combination drug was trastuzumab. The overall incidence of adverse drug reactions was 63.5% (431/679 patients) in patients treated with S-1 alone, and 55.9% (66/118 patients) in patients treated with S-1 + trastuzumab., Conclusions: Monotherapy with S-1 or combination therapy with S-1 + trastuzumab was well tolerated for inoperable or recurrent breast cancer patients.

Purpose: Adjuvant high-dose chemotherapy (HDC) with autologous hematopoietic stem-cell transplantation (AHST) for high-risk primary breast cancer has not been shown to prolong survival. Individual trials have had limited power to show overall benefit or benefits within subsets., Methods: We assembled individual patient data from 15 randomized trials that compared HDC versus control therapy without stem-cell support. Prospectively defined primary end points were relapse-free survival (RFS) and overall survival (OS). We compared the effect of HDC versus control by using log-rank tests and proportional hazards regression, and we adjusted for clinically relevant covariates. Subset analyses were by age, number of positive lymph nodes, tumor size, histology, hormone receptor (HmR) status, and human epidermal growth factor receptor 2 (HER2) status., Results: Of 6,210 total patients (n = 3,118, HDC; n = 3,092 control), the median age was 46 years; 69% were premenopausal, 29% were postmenopausal, and 2% were unknown menopausal status; 49.5% were HmR positive; 33.5% were HmR negative, and 17% were unknown HmR status. The median follow-up was 6 years. After analysis was adjusted for covariates, HDC was found to prolong relapse-free survival (RFS; hazard ratio [HR], 0.87; 95% CI, 0.81 to 0.93; P < .001) but not overall survival (OS; HR, 0.94; 95% CI, 0.87 to 1.02; P = .13). For OS, no covariates had statistically significant interactions with treatment effect, and no subsets evinced a significant effect of HDC. Younger patients had a significantly better RFS on HDC than did older patients., Conclusion: Adjuvant HDC with AHST prolonged RFS in high-risk primary breast cancer compared with control, but this did not translate into a significant OS benefit. Whether HDC benefits patients in the context of targeted therapies is unknown.

There are four members of the ErbB family: the epidermal growth factor(EGF)receptor(also called HER1 or EGFR), HER2, HER3 and HER4. Dimerization is the process whereby two HER receptor molecules associate to form a noncovalent complex. HER dimers are the active receptor forms required for transmission of external stimuli to the interior of the cell. HER dimerization occurs upon ligand binding and both HER homodimers and heterodimers can be formed in the process. However, HER2 appears to be the preferred dimerization partner of the other HER family members. Fifteen∼20% of all breast cancers are HER2 positive and have a poor prognosis. Trastuzumab is an excellent, rationally-designed targeted cancer treatment. It is a recombinant, humanized, anti-HER2 monoclonal antibody that specifically binds to the extracellular area of HER2. However, the overall trastuzumab response rate is low, and the causes of trastuzumab resistance are poorly understood. Thus, there is a need for alternative anti-HER2 strategies for trastuzumab-resistant disease. Lapatinib is an orally administered small-molecule, reversible inhibitor of both EGFR and HER2 tyrosine kinase, and its activities include subsequent inhibition of its down- stream MAPK-ERK1/2, and the AKT signaling pathway. Lapatinib is more active when used in combination with capecitabine. For women with trastuzumab pre-treated HER2-positive breast cancer, Here, I will review the basics of EGFR and HER, and the treatment strategy for HER2-positive breast cancer with lapatinib.

We describe a patient with human epidermal growth factor receptor type 2 (HER2/c-erbB-2)-positive metastatic breast cancer who survived for approximately 6 years after the initiation of combination therapy with trastuzumab and varying types of chemotherapeutic agents. The patient was a 48-year-old postmenopausal female who underwent partial mastectomy with axillary node dissection for cancer of the right breast in March 1994. She developed lung metastases 2 years thereafter, but survived free of relapse for 8 years following chemotherapy and pulmonary lobectomy. The patient failed to respond to lapatinib, a HER1 (EGFR)/HER2 tyrosine kinase inhibitor, received during the course of her treatment but then again responded to subsequently administered trastuzumab. Primary treatment with trastuzumab and paclitaxel was initiated in April 2004 when the patient developed hepatic metastases 8 years after undergoing surgery for lung metastases. Long-term combination therapy with continued trastuzumab and a variety of chemotherapeutic agents was administered for 6 years without any significant adverse events. We discuss the treatment strategies for HER2-positive breast cancer and the role of lapatinib, a recently approved anticancer drug.

Background: HER2-positive metastatic breast cancer (MBC) relapsing after trastuzumab-based therapy may require continued HER2 receptor inhibition to control the disease and preserve the patients' quality-of-life. Efficacy and safety of lapatinib monotherapy was evaluated in Japanese breast cancer patients after trastuzumab-based therapies., Methods: In studies, EGF100642 and EGF104911 evaluated the efficacy and safety of oral lapatinib given 1500 mg once daily in patients with advanced or MBC. All patients progressed on anthracyclines and taxanes; HER2-positive patients had also progressed on trastuzumab., Results: For HER2-positive tumours (n=100), objective response rate was 19.0% (95% confidence interval (CI): 11.8-28.1) and clinical benefit rate (CBR) was 25.0% (95% CI: 16.9-34.7). One out of 22 HER2-negative tumour was documented as complete response (n=22). The median time-to-progression (TTP) in the HER2-positive and HER2-negative groups was 13.0 and 8.0 weeks (P=0.007); median overall survival was 58.3 and 40.0 weeks, respectively. The most frequent adverse event was diarrhoea. TTP and CBR were significantly associated with HER2 expression. Patients with tumours harbouring an H1047R PIK3CA mutation or low expression of PTEN derived clinical benefit from lapatinib., Conclusion: Lapatinib monotherapy had shown anti-tumour activity in Japanese patients with HER2-positive MBC that relapsed after trastuzumab-based therapy, including those with brain metastases. Patients benefiting from lapatinib may have biomarker profiles differing from that reported for trastuzumab.

Background: Trastuzumab (Herceptin®) was clinically introduced in Japan in 2001 to treat metastatic breast cancer patients who show an over-expression of human epidermal growth factor receptor 2 (HER2). Since that time, this anticancer drug has played an important role in the treatment of cancer. In the present retrospective study, trastuzumab was administered in combination with 5'-deoxy-5-fluorouridine (5'-DFUR) and cyclophosphamide (CPM) as the third- to sixth- line therapy in 25 patients whose HER2-positive metastatic breast cancers did not respond but showed recurrence after treatment with several chemotherapeutic regimens, namely, trastuzumab alone, and trastuzumab combined with taxane or other anticancer drugs., Methods: Trastuzumab was administered at a dose of 2 mg/kg (at a loading dose of 4 mg/kg) once weekly; 5'-DFUR, at an oral daily dose of 800-1200 mg/body; and CPM, at an oral daily dose of 100 mg/body for 2 weeks followed by one week discontinuation of the drug., Results: The response rate to the combination therapy was 32% (95% confidence interval, 17-52%). Grade 3 adverse effects, according to National Cancer Institute-Clinical Therapeutic Conference version 2.0. (NCI-CTC ver. 2.0), included: neutropenia in 7 patients, anemia in one, and elevation of alkaline phosphatase (ALP) in one. Other adverse events of grade 1 or 2 in accordance with NCI-CTC included general fatigue, nausea, vomiting, thrombocytopenia, increased transaminase, and decreased serum albumin. All adverse events were easily controllable and reversible after discontinuation of the drug., Conclusions: Combination therapy with trastuzumab, 5'-DFUR and CPM is effective and well tolerated as the third- to six line treatment option for patients with HER2-overexpressing metastatic breast cancer., Mini-Abstract: Combination therapy by trastuzumab with 5'-DFUR and cyclophosphamide can be safely administered on an outpatient basis and is useful to treat patients with HER2-overexpressing metastatic breast cancer.

Currently, trastuzumab is one of the key drugs in the treatment strategy for HER2-positive breast cancer. Although metastatic breast cancer is unlikely to be cured, some HER2-positive patients have survived for a long time with complete response to trastuzumab therapy. In HER2-positive metastatic breast cancer, single agent trastuzumab is effective and less toxic. Combination of trastuzumab with cytotoxic drugs is also effective. Therefore, major guidelines recommend using trastuzumab as a key drug in the management of HER2-positive metastatic breast cancer. However, many clinical questions still need to be solved. In this article, recent evidence was reviewed to find some answers about these issues.

Background: Fibroblast growth factor 8-isoform b (FGF8b) has been detected in human clinical sex-organ related cancers including hormone-refractory prostate cancer. There are, however, few relevant experimental models. A murine monoclonal anti-FGF8 antibody, KM1334, has been shown to neutralize FGF8b and inhibit the growth of androgen-dependent mouse mammary SC-3 cells in vitro and in vivo. In the present study, we evaluated the anti-tumor activity of KM1334 against androgen-dependent and -independent progression of FGF8b-expressing human prostate cancer xenografts., Methods: FGF8b cDNA was transfected into androgen-dependent human prostate cancer cell line LNCaP, and its xenograft tumors were established subcutaneously in SCID mice with or without castration. KM1334 at the dose of 400 microg/head was injected twice weekly., Results: FGF8b-expressing LNCaP cells secreted FGF8b, showed enhanced level of Erk1/2 phosphorylation, and showed more potent growth properties than mock-expressing cells in vitro and in vivo. KM1334 reduced these properties in vitro, inhibited tumorigenecity in vivo (T/C=0.33), and showed anti-tumor activity against established tumors (T/C=0.47) of FGF8b-expressing cells. FGF8b-expressing LNCaP tumors were androgen-dependent. However, they recurred as androgen-independent FGF8b positive tumors after castration. KM1334 also inhibited the growth of established FGF8b-expressing tumors in the androgen-independent states (T/C=0.47)., Conclusions: These results indicate that humanized monoclonal antibodies, conserving the paratope of KM1334, are a promising candidate for therapy of FGF8b-expressing clinical prostate cancers. Follow-up studies using xenograft models with clinical FGF8b-expressing tumors are required to validate these early findings.

HER2 gene is overexpressed or amplified in approximately 30% of breast cancer. Breast cancer patients with HER2-overexpression or amplification have shortened disease free and overall survival. The HER2 protein is a useful target for antibody therapy of cancers overexpressing the HER2 gene. Since the recombinant humanized anti-HER2 monoclonal antibody, trastuzumab (Herceptin) was introduced into clinical practice, trastuzumab has become one of the key drugs in the treatment for HER2 positive metastatic breast cancer(MBC). However, much controversy exists on the optimal use of trastuzumab. In this paper, positioning of trastuzumab in the treatment algorithm for HER2 positive MBC as well as early breast cancer will be reviewed and discussed on the basis of our experience.

Background: Oxaliplatin is a newly developed antitumor platinum complex that is known to have low nephrotoxicity. The inhibitory effects of oxaliplatin on several tubular functions were compared with those of cisplatin and carboplatin, using a renal cortical slice system., Methods and Results: Rat renal cortical slices were incubated with 0.25 mM to 2.0 mM of oxaliplatin, cisplatin, on carboplatin at 37 degrees C for 120 min. Para-amino hippuric acid (PAH) accumulation, gluconeogenesis, and ATP content in the rat renal slices were determined. PAH accumulation was not inhibited by carboplatin, but it was significantly inhibited by oxaliplatin and cisplatin. Inhibition of PAH accumulation by cisplatin was greater than that by oxaliplatin. Gluconeogenesis was not decreased by carboplatin, but it was suppressed by oxaliplatin and cisplatin in a dose-dependent manner. The decrease in gluconeogenesis induced by oxaliplatin was significantly greater than that induced by cisplatin. ATP content in the renal slices was decreased by oxaliplatin, cisplatin, and carboplatin to almost the same extent. As an in vivo experiment, 21.6 mmole/kg of oxaliplatin, cisplatin, or carboplatin was injected into rats; then blood urea nitrogen (BUN) and serum creatinine were determined on day 4. Significantly elevated levels of BUN and serum creatinine were observed only in the rats injected with cisplatin., Conclusions: Oxaliplatin did not cause nephrotoxicity in the in vivo study; however, the nephrotoxic pattern of oxaliplatin observed in the renal cortical-slice system resembled that of cisplatin. The reason why oxaliplatin is less nephrotoxic than cisplatin in vivo could not be fully elucidated in the present experiment using the renal cortical-slice system.

The HER2 gene is overexpressed or amplified in approximately 30% of breast cancers. Breast cancer patients with HER2 overexpression or amplification have shortened disease-free and overall survivals. The HER2 protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER2 gene. The recombinant humanized anti-HER2 monoclonal antibody, trastuzumab (Herceptin) is now available for clinical use. In a large phase II trial, trastuzumab produced a favorable response rate as a single agent in patients with metastatic breast cancer who had received one or two prior chemotherapies. Furthermore, a large phase III trial showed that trastuzumab plus chemotherapy as a first-line treatment for metastatic breast cancer significantly improved response rate, time to disease progression, and overall survival compared with chemotherapy alone. As a single agent and in combination with chemotherapy, trastuzumab was generally well tolerated. Thus, trastuzumab plays an important role in the treatment strategy of metastatic breast cancer overexpressing HER2 protein. In this article, details of this novel biologic agent are reviewed, in conjunction with an overview of clinical studies performed in Japan.

Cancer patients receiving chemotherapy have an increased risk of developing cardiovascular complications even if they have normal hearts, and the risk is greater if there is known history of heart disease. Various clinical cardiac complications that have been reported are arrhythmias, cardiomyopathy, vaso-occlusion or vasospasm resulting in angina or myocardial infarction. It is well know that cardiovascular complications in oncology patients is caused by anthracyclines. The trastuzumab as the new treatment option for the metastatic breast cancer may be associated with the development of a clinically significant cardiotoxicity. We described and reviewed the cardiotoxicity in oncology patients.

Herceptin (trastuzumab) is a recombinant humanized murine monoclonal antibody that recognizes HER2/neu cell-surface receptors and has been shown to be active both in combination with adriamycin (epirubicin)/cyclophosphamide or taxanes and as a single agent, either in the 1st or 2nd/3rd line treatment of women with metastatic breast cancer with HER2 overexpression by IHC or gene amplification by FISH. Preliminary results of Herceptin with other agents such as vinorelbine, cisplatin and various hormonal agents are also promising, and these combinations warrant further clinical exploration. Large-scale multicenter trials including a European and an international study in adjuvant setting have started for high-risk women with HER2 overexpressing breast cancer, with total planned recruitment of nearly 10,000 women.

The HER 2/neu protein is thought to be a unique and useful molecular target for antibody therapy of cancers overexpressing the HER 2/neu gene. The recombinant humanized anti-HER 2 monoclonal antibody trastuzumab (Herceptin) has been available for clinical use in metastatic breast cancer in Japan since June 2001. Some breast cancer patients have responded to trastuzumab alone. A phase III study showed significant efficacy of combination use with paclitaxel compared with paclitaxel alone. Trastuzumab has some toxicities including infusion reaction and cardiotoxicity. It is very rare that infusion reaction manifests lethally. Although trastuzumab should not be concurrently used with an anthracycline, cardiotoxicity was also identified in patients treated with trastuzumab alone. The cumulative dose of anthracycline has not yet been identified as a risk factor, but patients who have received a high cumulative dose should be treated with special caution. In this article, the details of this novel biologic agent are reviewed from basic and clinical studies.

This is a case report of a 57-year-old woman with a history of primary carcinoma of the right breast with metastases to the contralateral axillary lymph node. After a partial response (PR) was induced by high-dose chemotherapy with peripheral blood stem cell transplantation, she underwent mastectomy with biopsy of the bilateral axillary lymph nodes. Six months after surgery, the patient had multiple lung metastases. She was then treated with five cycles of fluorouracil, mitoxantrone and vindesine. Although a PR was achieved, further chemotherapy could not be given because of cardiac dysfunction. Since immunohistochemical staining for the HER2 gene product was strongly positive on the surface of primary tumor cells, humanized anti-HER2 monoclonal antibody (trastuzumab) was given intravenously. The metastatic lesion decreased in size and finally appeared to be only cicatricial. Twenty-one months after the initial administration of trastuzumab, the pulmonary lesion was excised. The pathological examination revealed no tumor cells in the resected specimen so further treatment was stopped. The relapse-free state has continued for 24 months after the pulmonary resection.

The HER-2/neu protein is thought to be a unique and useful target for antibody therapy of cancers overexpressing the HER-2/neu gene. The recombinant humanized anti-HER-2 monoclonal antibody, trastuzumab (Herceptin) was approved for clinical use in the US in 1998. In Japan, it was approved and later became available in June, 2001. We have treated 41 patients with metastatic breast cancer with trastuzumab purchased from the US. In this paper, the details of the patients we experienced are reviewed.

Malignant cystosarcoma phyllodes (MCSP) is a rare breast tumor. Chemotherapeutic regimens for treatment of MCSP have not been established. We previously established an MCSP xenograft line MC-3-JCK. In this study, we established a new MCSP xenograft line, MC-10-JCK, by serial transplantation in nude mice. We studied the chemosensitivity of these two MCSP tumor xenografts to anticancer drugs in vivo. We also examined the expression of multidrug resistance-related proteins such as p-glycoprotein (Pgp) and multidrug resistance-associated protein (MRP) by immunohistochemical analysis. These two xenografts were sensitive to doxorubicin, vincristine and cyclophosphamide in vivo. Immunohistochemically, clinical specimens and xenografts were negative for Pgp and MRP expression. These results are consistent with the chemosensitivity of human MCSP to lipophilic anticancer compounds.

The importance of dose intensity in breast cancer chemotherapy has been stressed in recent years with clear correlations demonstrated between dose intensity and clinical outcome of the patients in both therapeutic and adjuvant settings. In addition to various and intense supportive care, autologous stem cell support (ASCS) has been used over the past 15 years in order to overcome myelotoxicity of cancer chemotherapy. ASCS was initially practiced in the form of bone marrow transplantation, and more recently peripheral stem cell transplantation has been combined in addition to administration of G-CSF. Our pilot study in patients with recurrent/advanced breast cancer showed a higher response rate and a higher survival rate as compared to conventional chemotherapy, and there have been some long-term disease-free survivors with probable cures among complete responders with ASCS-supported chemotherapy. In adjuvant settings for patients with a high risk for recurrence who had been given a high-dose, the ASCS-supported regimen showed a higher disease-free survival rate as compared to those who were treated with conventional adjuvant therapy. Whether these apparently better results in our pilot studies hold true generally remains to be seen with well-scheduled randomized clinical trials.

High-dose chemotherapy supported by autologous bone marrow transplantation (ABMT) was given 34 times on twenty six patients with solid tumor. Excluding 6 patients with adjuvant use and 2 patients with non-evaluable lesion, the response rate (CR + PR) of 44.4% was observed among 18 evaluable patients with advanced solid tumor. The results seem to be quite significant since many of the patients had become refractory to conventional treatments and intensity of chemotherapy was still moderate in some of the patients. ABMT following a course of chemotherapy is a promising approach of overcoming the toxic limitations of intensive chemotherapy since a dose-response relationship exists in many situations of cancer chemotherapy and ABMT appears to prevent fatal myelosuppression.