Tumor proliferative activity and response to first-line chemotherapy in advanced breast carcinoma

Summary The relationship between tumor proliferative activity and response to first-line chemotherapy and survival was investigated in 76 advanced breast cancer patients. Proliferative activity was determined by means of Ki-67 immunohistologic staining on primary tumors (55 patients) or at the relapse site (21 patients), and was classified as low ( 25% of stained cells) or high (> 25% of stained cells). The usual WHO response criteria were used. The median duration of follow-up was 18 months (range 3–58).Forty-seven patients (62%) had tumors with low, and 29 (38%) had tumors with a high rate of proliferative activity. The two groups were well balanced in terms of important variables such as disease-free survival, performance status, age, menopausal status, and the type of first-line chemotherapy (anthracycline-based regimens versus cyclophosphamide-methotrexate-5-fluorouracil). The estrogen receptor (ER) content, measured by means of immunohistochemical assay, was markedly different in the two groups, with 27/47 tumors with low proliferative activity (57%) and 6/29 with high-proliferative activity (21%) being ER positive ( 45% of stained cells) (p = 0.003). Moreover, a significant difference in the metastatic pattern was also evident, with a higher incidence of bone and a lower incidence of soft tissue metastases in the group of patients with tumors with low proliferative activity (p = 0.004). Overall, 10/47 responses (21%: PR = 7, and CR = 3) were observed in the group with a low rate of proliferative activity, versus 14/29 (48%: PR = 9, and CR = 5) in the group with highly proliferative tumors, the difference being statistically significant (p = 0.03). When a multivariate analy-sis was performed, the only factor that retained independent prognostic significance was the predominant site of disease, particularly soft tissues (p = 0.003). Despite the difference in response rate, when survival analysis was performed according to the Kaplan-Meier method, no significant difference was observed in the two groups, but when the analysis was limited to responsive patients, the median survival observed in those with a low and those with a high rate of proliferation was 35 and 19 months respectively (p = 0.02). The same results were obtained when multivariate survival analysis was carried out using Cox's regression model. These data suggest that there is a link between tumor proliferative activity and response to chemotherapy in advanced breast cancer, and may indicate the need to use more intensive treatments in selected patients with highly proliferative tumors.Presented in part at the Annual Meeting of the American Society of Clinical Oncology, May 14–17, 1994, Dallas, TX, USA     

多西他赛二线治疗23例晚期非小细胞肺癌

目的：评价单药多西他赛[泰索帝)作为二线化疗耐晚期非小细胞肺癌(NSCLC)的疗效和不良反应，方法：23例经病理和(或)细胞学诊断的晚期非小细胞肺癌．曾用含铂类方案化疗，治疗后复发或进展．接受泰素帝75mg/m^2静滴1小时．第1天．每3周重复。结果：可评价疗效23例中．无完全缓解（CR)，部分缓解(PR）17％(4／23)，稳定(SD)57％(13／23)，进展(PD)26％(6／23)，有效率17％(4／23)；中位生存期9个月，一年生存率39％(9，23)。不良反应主要是血液学毒性，但患者可以耐受。结论：泰素帝草药用于二线化疗治疗晚期非小细胞肺癌疗效肯定．耐受性较好。     

来曲唑与氨鲁米特对照治疗绝经后晚期乳腺癌113例

目的对比来曲唑和氨鲁米特治疗妇女绝经后晚期乳腺癌患者的有效性和耐受性。方法采用开放、随机、多中心对照研究。患者随机分组接受口服来曲唑2.5mg.d~(-1)或氨鲁米特1g.d(-1)的对照治疗。结果来曲唑组(n=59)有效率23.73%(CR 2例,PR 12例,ITT 有效率21.88%),SD 20.31%(13例)。氨鲁米特组(n=54)有效率11.11%(CR 1例,PR 5例,ITT 有效率10.17%),SD 20.34%(12例),2组疗效无统计学差异(P>0.05)。来曲唑组和氨鲁米特组不良反应发生率分别为18.64%和42.11%,与治疗相关的不良反应发生率分别为13.56%和33.33%。比较2组总的和与治疗相关的不良反应发生率均以来曲唑组明显较低,P 值均为0.002。结论来曲唑对绝经后、ER/PR 阳性或不明的晚期乳腺癌患者有效率为23.73%,与氨鲁米特比较无统计学差异。但来曲唑不良反应较氨鲁米特明显低,可以代替氨鲁米特用于晚期绝经后受体阳性或不明乳癌患者的治疗。     

A trial-based cost-effectiveness analysis of letrozole followed by tamoxifen versus tamoxifen followed by letrozole for postmenopausal advanced breast cancer.

BACKGROUND: Third-generation aromatase inhibitors are being considered as an alternative to tamoxifen as first-line therapy for advanced breast cancer. These newer therapies are more expensive, and will gain greater acceptance if they can demonstrate cost-effectiveness. METHODS: Life table analyses are used to compare the costs and benefits [life years gained and quality-adjusted life years (QALYs) gained] of treating postmenopausal women with advanced breast cancer with first-line letrozole (with the option of second-line tamoxifen) compared with first-line tamoxifen (with the option of second-line letrozole). Patient-level data from a large clinical trial describes the effectiveness of the therapy options, clinicians estimate resource usage and utility values are obtained from the literature. RESULTS: The mean cost of providing first- and second-line hormonal therapy is pound 4765 if letrozole is the first-line therapy and pound 3418 if tamoxifen is provided first (a difference of pound 1347). However, patients receiving letrozole as first-line therapy gain an additional 0.228 life years, or 0.158 QALYs. The cost-effectiveness analysis found that first-line hormonal therapy with letrozole gains additional life years at a cost of pound 5917, whilst the cost per additional QALY gained is pound 8514. CONCLUSION: The strategy of letrozole as first-line hormonal therapy not only provides an opportunity for extending and improving patient's quality of life, but also is highly cost-effective compared with other generally accepted medical treatments.     

Locally advanced/inflammatory breast cancers treated with intensive epirubicin-based neoadjuvant chemotherapy: are there molecular markers in the primary tumour that predict for 5-year clinical outcome?

BACKGROUND: Locally advanced and/or inflammatory breast cancer (LABC) is a heterogeneous disease. Molecular markers may help to understand this heterogeneity. This paper reports the results of a study assessing the potential prognostic or predictive value of HER-2, p53, cyclinD1, MIB1, ER and PgR expression by immunohistochemistry from patients included in an EORTC-NCIC-SAKK trial. PATIENTS AND METHODS: A total of 448 patients with a cytological or histological diagnosis of LABC were randomised into a trial comparing two anthracycline-based neoadjuvant regimens. Chemotherapy was followed by standard locoregional therapy. Survival was comparable in both arms. We collected and analysed centrally paraffin-embedded tumour specimens from 187 (72.5%) of 258 patients that had a histological diagnosis. RESULTS: Of the patients included in this molecular marker study 114 relapsed and 91 died. In the multivariate analysis p53 positivity was associated with a shorter progression-free survival [hazard ratio (HR) = 1.96; 95% CI 1.33-2.91; P = 0.0008) and a shorter overall survival (HR = 1.98; 95% CI 1.28-3.06; P = 0.002). PgR positivity predicted for a longer overall survival (HR = 0.54; 95% CI 0.35-0.83; P = 0.0045). CONCLUSIONS: p53 was an independent factor predicting for survival. In order to clarify whether p53 is a pure prognostic and/or a predictive factor, a phase III trial is being conducted (EORTC 10994/BIG 00-01 study) using functional assay in yeast from frozen tumour samples.     

抗癌宝口服液治疗中晚期恶性肿瘤103例临床观察

目的：观察中药抗癌宝口服液治疗中晚期恶性肿瘤临床效果。方法：１０３例患者随机分为抗癌宝观察组与化疗对照组，对两组疗效作比较。结果：观察组患者免疫功能，近期有效率（ＣＲ＋ＰＲ），生存质量，１、２、３年生存期及中位生存时间，癌胚抗原下降水平，明显高于对照组，且有显著性差异。结论：抗癌宝具有抑制肿瘤生长，延长生存时间，提高生存质量之效。     

Durable remission of locally advanced breast cancer with multimodality management

We treated 20 women with locally advanced breast cancer between January 1991 and September 1996, The treatment regimen included 4 cycles of intensive doxorubicin (30 mg/m2/ d on 3 consecutive days every 2 weeks with G-CSF support), followed by appropriate surgery, followed by high dose therapy with cyclophosphamide, carboplatin and thiotepa (STAMP V, CTCb). Of the 20 patients, seven presented with inflammatory breast cancer, three with Stage HIB, seven with stage IIIA, one with multifocal Stage IIB and two with Stage IV M1 (ipsilateral supraclavicular lymph node involvement) (including one who had an inflammatory primary) disease. Six patients had not undergone mastectomy at the time of entering the protocol. These six received the doxorubicin in a neoadjuvant fashion and were thus evaluable for tumor response. The remaining 14 received doxorubicin as adjuvant therapy prior to intensification and transplantation. All patients underwent local-regional radiation therapy and were placed on oral tamoxifen. Doxorubicin was well tolerated in this schedule with ali but three patients receiving all their cycles on schedule. Both BM and PBPC were easily collected after this regimen and, when reinfused, resulted in the prompt recovery of granulocytes (median 11 days to 500 absolute granulocyte count) and platelets (median 13 days to 20000 platelets). The six patients who received doxorubicin prior to mastectomy all had major clinical responses, but were found to have microscopic focii of breast cancer in the mastectomy specimens. The overall treatment was well tolerated with the exception of one treatment-related death (5%). The overall and relapse free survival are 70% and 58% respectively with a median follow-up of 40 months (range 12–74 months). When the Stage IV patients are censored, the relapse-free survival rate is 69%. In the bone marrow transplant phase of treatment, the major non-hematologic toxicities were stomatitis (70%) and anorexia requiring parental nutrition (75%).     

Advanced glycosylation end products, protein kinase C and renal alterations in diabetic rats

Objective To study the relationship between advanced glycosylation end products (AGE) an d protein kinase C (PKC), and their effects on renal alteration in diabetic rats .
Methods Insulin or aminoguanidine was administered to diabetic rats. Blood glucose, hem oglobin A_1C (HbA_1C), glomerular tissue extracts AGE (GTE-AGE), PKC, glomerular basement membrane thickness (GBMT) and urine protein/creatinine ( Pr/Cr) ratio in diabetic rats were measured and analysed.
Results Levels of blood glucose, HbA_1C and AGE, PKC activity, the Pr/Cr ratio an d GBMT were all significantly increased (P values all less than 0.01) in di abetic rats. Insulin could decrease the formation of HbA_1C and AGE, and improve PKC activity. Aminoguanidine had no influence on PKC activity (P >0.05) although it decreased the formation of AGE. Both drugs could delay t he increase of urine Pr/Cr ratio and GBMT (P<0.05 or P<0.01).
Conclusions Chronic hyperglycemia may lead to an increase of PKC activity. HbA_1Cand AGE may not directly contribute to alterations of PKC activity, but the increa se of PKC activity could promote the action of AGE on GBM thickening. It is imp ortant t o inhibit the formation of AGE and reduce the PKC activity so as to prevent or d elay the development of diabetic nephropathy.     

Oxaliplatin as single agent in previously untreated colorectal carcinoma patients: A phase II multicentric study

Background: Oxaliplatin is a new cytotoxic agent from the diaminocyclohexane family with proven antitumor activity against colon cancer cell lines. Activity in patients with colorectal carcinoma previously treated with 5-fluorouracil has been studied in three single-agent phase II trials, showing a reproducible response rate of 10%. Here we report a phase II trial with oxaliplatin as a first-line chemotherapy for metastatic colorectal cancer.Patients and methods: Twenty-five patients were entered in the study. All of them had metastatic disease without previous chemotherapy, and at least one lesion had to be measurable by computed tomography (CT). Therapy consisted of a two-hour infusion of oxaliplatin at a dose of 130 mg/m² every 21 days.Results: The overall response rate determined by investigators was 20% (95% CI, 6.8%–40.7%). Eight patients (32%) had stable disease. The median time to disease progression in responders was six months (range four to nine). The median progression-free survival was four months and median overall survival 14.5 months (95% CI, 10–20 months). The main toxic effects were peripheral neuropathy (92%) and laryngopharyngeal dysesthesia (75%). No severe grade 3–4 neurotoxicities (NCI-CTC) were found. Gastrointestinal and hematological toxicities were mild.Conclusions: Oxaliplatin is an active agent in first-line chemotherapy for advanced colorectal cancer. It was well tolerated, caused no toxic deaths, had low hematotoxicity, well controlled gastrointestinal toxicity, and frequent but mild peripheral neurological symptoms. Therefore, it is of interest to associate oxaliplatin with other active compounds.