Comparative trial of endocrine versus cytotoxic treatment in advanced breast cancer.

Ninety-two women with advanced breast cancer were allocated at random to receive either cytotoxic or endocrine treatment. Out of 45 women included in the cytotoxic treatment group, 22 (49%) achieved complete or partial remission of their disease, whereas of the 47 included in the endocrine treatment group, only 10 (21%) achieved such remission. Significantly longer survival times in the cytotoxic treatment group were most apparent among premenopausal women, 75% of such patients responding to cytotoxic drugs (median survival 46 weeks) compared with only 11% benefiting from ovarian ablation (median survival 12 weeks). In postmenopausal women with predominantly soft-tissue disease, however, additive hormonal treatment with tamoxifen produced remission rates and survival times equivalent to those produced by cytotoxic drugs.     

Cytokinetic parameters of locally advanced human breast cancer treated with diethylstilbestrol and chemotherapy

Thirty-six patients with locally advanced breast cancer received diethylstilbestrol (1 mg/die) for 3 days followed by FAC (5 Fu 600 mg/m2, adriamycin 50 mg/m2, cytoxan 600 mg/m2) on day 4, q. 21 days. After three cycles, responsive patients were submitted to surgery. Tumor kinetic parameters were evaluated by TLI and PDP-LI in 22 patients on serial tumor biopsies at diagnosis (TO), after DES (T1), 24 hrs after the first FAC (T2) and at the time of radical surgery (T3). An estrogenic recruitment was evident by TLI in 9/22 tumors and by PDP-LI in 16/22 patients. Our results demonstrate that diethylstilbestrol can induce a kinetic recruitment of breast cancer cells independently from their ER content and that chemotherapy is able to stop cell proliferation.     

4-Hydroxyandrostenedione treatment for postmenopausal patients with advanced breast cancer

We have treated 128 postmenopausal women with advanced breast cancer with 4-hydroxyandrostenedione. Of these, 118 were assessable for toxicity and 100 for response to treatment. Response to therapy was seen in 34% of patients and stabilization of disease in 12 patients. Three dose regimens were used (500 mg intramuscularly weekly; 250 mg intramuscularly every 2 weeks; and 500 mg orally daily). There was no difference in response in these three groups. Side effects were minimal and local reaction to injected drug was seen in 13% of patients. The sole severe side effect observed was neutropenia which was transient and reversible on discontinuing therapy. 4-Hydroxyandrostenedione is an effective nontoxic agent in the treatment of breast cancer.     

The immunologic aspects in advanced ovarian cancer patients treated with paclitaxel and carboplatin chemotherapy

Till now, little is known about the effects of chemotherapy on the immunity of cancer patients and the ideal timing (“window” period) for immunotherapy combined with chemotherapy. In this study, we addressed the immunogenicity of apoptotic ovarian cancer cells induced by paclitaxel and carboplatin, the immunologic aspects in ovarian cancer patients under chemotherapy, and the CTL response when CD8⁺ T cells were stimulated with tumor antigen in the “window” period. The immunogenicity of apoptotic ovarian cancer cells was detected first. Then, blood samples from each ovarian cancer patient were obtained before (S₀) and at days 5–7 (S₁), days 12–14 (S₂) and days 25–28 (S₃) after chemotherapy. The proportions of immunocyte subsets and the function of NK cells were studied. We found that apoptotic ovarian cancer cells elicited a powerful CTL response with antitumor activity in vitro. The proportions of CD3⁺ T cells, CD4⁺ T cells and the ratio of CD4⁺ to CD8⁺ cells did not change significantly on S₁, S₂ and S₃, compared to S₀, whereas the percentage of Treg cells decreased remarkably on S₂. The proportions of Th1, Tc1, CD45RO memory T, NKT cells and the ratio of Tc1 to Tc2 cells increased significantly on S₂. IFN-γ secreting CD8⁺ T cells also increased remarkably on S₂, especially when CD8⁺ T cells were stimulated with autologous tumor antigen. From our point of view, chemotherapy induces temporary immune reconstitution and augments anti-tumor immune response. It is probable that the “window” period of days 12–14 after chemotherapy provides the best opportunity for immunotherapy.     

肠道微生物群落与晚期大肠癌化疗患者预后的关系

目的分析肠道微生物群落与大肠癌化疗患者预后的相互关系。方法选取2013-2016年符合晚期大肠癌诊断标准的106位患者,采用随机数字表法将其分为实验组和对照组。对照组予以奥沙利铂+希罗达(XELOX)方案化疗,实验组在对照组基础上口服双歧杆菌三联活菌胶囊至化疗结束。分别于化疗前后对两组患者肠道微生物群落进行微生物计数,并记录两组患者化疗后的不良反应。采用欧洲癌症研究与治疗组织生活质量问卷(EORTC QLQ-C30)评估患者治疗前后生活质量,随访并记录入组患者的总生存时间(OS)。结果两组在年龄、体重指数(BMI)、家族史等一般情况差异均无统计学意义(P0.05)。治疗前,两组患者各肠道微生物群落数量比较差异均无统计学意义(P0.05)。治疗后,实验组患者的双歧杆菌、乳酸杆菌、葡萄球菌数量较治疗前差异有统计学意义(P0.05),对照组双歧杆菌、乳酸杆菌、肠球菌数量较治疗前差异有统计学意义(P0.05)。与对照组比较,治疗后的实验组双歧杆菌、乳酸杆菌、葡萄球菌数量差异有统计学意义(P0.05),实验组患者恶心、呕吐及腹泻发病率显著降低(P0.05)。实验组中位生存期(MST)为37个月,对照组MST为26个月,治疗后患者生活质量有明显的好转(P0.05)。结论肠道微生物群落与晚期大肠癌化疗患者的预后有一定关系,益生菌治疗不仅可以降低大肠癌患者化疗后肠道并发症的发生率,还可以通过提高化疗的疗效提高患者的生存质量及生存时间。     

Phase II clinical study of high-dose toremifene in patients with advanced breast cancer

Thirteen postmenopausal women with advanced local or metastatic breast cancer were treated with the antiestrogen toremifene at a daily dose of 200 mg. All patients had failed previous treatment with different types of endocrine therapy and/or cytotoxic drugs. Objective response was only seen in one patient. Treatment was usually well tolerated but in three cases the drug had to be withdrawn due to side effects.     

Diffuse optical spectroscopy evaluation of treatment response in women with locally advanced breast cancer receiving neoadjuvant chemotherapy

The aim of this study was to investigate the potential of diffuse optical spectroscopy for monitoring of patients with locally advanced breast cancer (LABC) undergoing neoadjuvant chemotherapy. Fifteen women receiving treatment for LABC had the affected breast scanned before; 1 week, 4 weeks, and 8 weeks after treatment initiation; and before surgery. Optical properties related to tissue microstructure and biochemical composition were obtained. Clinical and pathologic tumor response was evaluated using whole-mount pathology after mastectomy. Patients who responded to treatment demonstrated an initial increase followed by a drop in optical parameters measured in the whole breast, whereas nonresponding patients demonstrated only a drop in the same parameters 1 week after treatment initiation. Responding patients demonstrated a significant increase of 17% ± 7%, 8% ± 8%, 10% ± 7%, 11% ± 11%, and 16% ± 15% in deoxygenated hemoglobin, oxygenated hemoglobin, total hemoglobin concentrations, water percentage, and tissue optical index, 1 week after treatment initiation, respectively. In contrast, nonresponding patients had a decrease of 14% ± 9%, 18% ± 7%, 17% ± 7%, 29% ± 7%, and 32% ± 9% in their corresponding optical parameters. Deoxygenated hemoglobin concentration (with 100% sensitivity, 83% specificity) and water percentage (with 75% sensitivity, 100% specificity) were found to be the best predictors of treatment response at 1 week after starting treatment. The results of this study suggest that optical parameters can be potentially used to predict and monitor patients' responses to neoadjuvant chemotherapy and can form a basis for the customization of treatments in which inefficacious treatments can be switched to more efficacious therapies.     

Natural cytotoxicity and interferon production in human cancer: deficient natural killer activity and normal interferon production in patients with advanced disease

Natural cytotoxicity was measured in 51 adult patients with solid epithelial malignant tumors and in 27 normal subjects. Peripheral blood leukocytes (PBL) from 31% of the patients and 7% of the controls failed to kill target cells (K562) in a short-term chromium-release assay. When patients were classified according to clinical stage, PBL from 12% of patients with localized cancers, but 50% of patients with advanced disease, failed to exhibit cytotoxicity within the normal range. Pretreatment of PBL with interferon alpha (IFN alpha) or with Newcastle Disease Virus (NDV), a potent inducer of IFN alpha, enhanced cytotoxicity from all normal subjects. Of patients whose PBL lacked spontaneous cytotoxicity, half were able to kill normally after pretreatment of PBL with IFN alpha or NDV. Virtually all the patients whose PBL were unable to kill despite pretreatment with IFN alpha or virus had disseminated malignancies. IFN alpha production by PBL exposed to NDV and to K562 cells was normal in all the patients regardless of stage of disease or ability to kill K562 cells. The observed defect in natural cytotoxicity is thus unlikely to be due to a failure of PBL to produce IFN alpha.     

Prevention of doxorubicin-induced alopecia by scalp cooling in patients with advanced breast cancer.

Scalp cooling with gel packs was used to try to prevent alopecia in 31 patients being treated with doxorubicin (Adriamycin), 29 for advanced breast carcinoma and two for carcinoid tumour. Twenty-eight of the 31 patients tolerated the procedure well, and 22 of these had either no hair loss or only slight loss which remained acceptable and did not require a wig. The main factor limiting success was biochemical impairment of liver function, which occurred in nine patients; of these, six had severe or total alopecia despite scalp cooling. Conversely, the technique was successful in all 19 patients with normal liver function. Carried out properly, this simple and effective technique greatly diminishes socially unacceptable alopecia associated with doxorubicin, and merits wider use.     

Concurrent or sequential use of cytotoxic chemotherapy and hormone treatment in advanced breast cancer: report of the Swiss Group for Clinical Cancer Research.

In a trial of combined hormone treatment and cytotoxic chemotherapy 464 patients with advanced breast cancer were randomly allocated to either concurrent or sequential treatment. Cytotoxic drugs were given only if the antitumour activity of the hormone treatment was inadequate. Hormone treatment consisted of oophorectomy for premenopausal and tamoxifen administration for postmenopausal patients. Length of survival was better, though not significantly, in premenopausal patients (p = 0.29) treated concurrently and in postmenopausal women (p = 0.17) treated sequentially; the difference was highly significant (p = 0.003) only for postmenopausal women in the low-risk category. The findings suggest that postmenopausal women with metastatic breast cancer should probably be treated primarily by carefully monitored hormone treatment.     

Serum levels of tumor necrosis factor alpha correlate with response to neoadjuvant chemotherapy in locally advanced breast cancer

It has been shown that serum levels of tumor necrosis factor alpha (TNF-alpha) are increased in breast cancer patients. There are few data available on the reduction of serum levels of this cytokine following chemotherapy. The aim of this study was to determine the effect of neoadjuvant chemotherapy on serum concentrations of TNF-alpha and the relation to response rates in locally advanced breast cancer. Twenty consecutive patients with non-inflammatory stage III-B breast cancer achieving a partial or complete clinical response to three courses of neoadjuvant chemotherapy followed by modified radical mastectomy were prospectively included in the study and evaluated. Sera were collected before the start and after the termination of chemotherapy. Serum concentrations of TNF-alpha were measured by an ELISA method. The pathological response rates were also evaluated and recorded. The control group consisted of 12 healthy age-matched women. The mean pre-treatment TNF-alpha value of breast cancer patients was 15.9 +/- 0.9 pg/mL while it was 5.8 +/- 1.7 pg/mL in the control group; the difference was statistically significant (p < 0.0001). The serum levels of TNF-alpha were markedly decreased in patients with partial and complete responses compared to pre-treatment values (p < 0.0001). There was also a difference in TNF-alpha levels in patients with partial vs complete responses (p < 0.0001). The relative change between pre- and post-treatment values correlated significantly with the type of response (p = 0.004). These results suggest that the serum concentration of TNF-alpha can be an indicator of response and could be used in clinical decision-making for patients with locally advanced breast cancer.     

A prognostic eight-gene expression signature for patients with breast cancer receiving adjuvant chemotherapy

Breast cancer is a popularly diagnosed malignant tumor. Genomic profiling studies suggest that breast cancer is a disease with heterogeneity. Chemotherapy is one of the chief means to treat breast cancer, while its responses and clinical outcomes vary largely due to the conventional clinicopathological factors and inherent chemosensitivity of breast cancer. Using the least absolute shrinkage and selection operator (LASSO) Cox regression model, our study established a multi-mRNA-based signature model and constructed a relative nomogram in predicting distant-recurrence-free survival for patients receiving surgery and following chemotherapy. We constructed a signature of eight mRNAs (IPCEF1, SYNDIG1, TIGIT, SPESP1, C2CD4A, CLCA2, RLN2, and CCL19) with the LASSO model, which was employed to separate subjects into groups with high- and low-risk scores. Obvious differences of distant-recurrence-free survival were found between these two groups. This eight-mRNA-based signature was independently associated with the prognosis and had better prognostic value than classical clinicopathologic factors according to multivariate Cox regression results. Receiver operating characteristic results demonstrated excellent performance in diagnosing 3-year distant-recurrence by the eight-mRNA signature. A nomogram that combined both the eight-mRNA-based signature and clinicopathological risk factors was constructed. Comparing with an ideal model, the nomograms worked well both in the training and validation sets. Through the results that the eight-mRNA signature effectively classified patients into low- and high-risk of distant recurrence, we concluded that this eight-mRNA-based signature played a promising predictive role in prognosis and could be clinically applied in breast cancer patients receiving adjuvant chemotherapy.     

Bacopasaponins with cytotoxic activity against human breast cancer cells in vitro

Molecular Biology Reports - Globally, breast cancer is a serious concern that exhibits a persistent rise in its incidence and related mortality even after significant advancement in the field of...     

Androgen depletion and repletion as a means of potentiating the effect of cytotoxic chemotherapy in advanced prostate cancer

Seventy-five patients with stage D-2 prostate cancer refractory to orchiectomy have been entered in a controlled trial to test whether androgen priming enhances the efficacy of chemotherapy. All patients are treated with aminoglutethimide and hydrocortisone as a means of achieving medical adrenalectomy and are given cyclic i.v. chemotherapy with cytoxan, adriamycin and 5-fluorouracil. Patients in the stimulation arm (N = 39) receive, in addition, fluoxymesterone (5 mg p.o. b.i.d.) for 3 days before and on the day of chemotherapy. A similar response rate was observed in the stimulation and control arm (83% vs 74% respectively) when the analysis was restricted to evaluable patients. When all patients were included, a significantly higher response rate was observed in the control arm (64% vs 49%, P less than 0.05) as a result of the larger fraction of unevaluable patients in the stimulation arm (41% vs 14%). Median duration of response is 9 months in the stimulation and 10 months in the control arm. Median overall survival in the stimulation and control group is 12 months and 16 months respectively. Significant toxicity consisting of exacerbation of bone pain and, in two patients, development of reversible spinal cord compression was observed following androgen priming. Our results suggest that combined medical adrenalectomy and chemotherapy are highly effective in the treatment of advanced prostate cancer. Thus far, no additional benefit has been observed with androgen priming.     

Effect on natural killer and antibody-dependent cellular cytotoxicity of adjuvant cytotoxic chemotherapy including melphalan in breast cancer

Natural killer (NK) cell activity and antibody-dependent (K) cell activity were studied sequentially in 30 patients with early node-positive breast cancer entered into an adjuvant chemotherapy trial. The drugs used were melphalan, and melphalan with methotrexate, given for 12 months. Estimations were made 3-monthly during chemotherapy, and then at 15 and 24 months to assess recovery. Mean values for NK-cell activity during chemotherapy were significantly lower than the mean pre-chemotherapy baseline value at all time-points from 3 to 15 months, but there was recovery by 24 months. Mean values for K-cell activity during chemotherapy did not appear to differ from the mean pre-chemotherapy value, but variability in individual values was high. Over a 4-year follow-up period, a comparison of 16 patients who did not develop recurrent breast cancer with 14 who did showed that NK-cell activity was significantly lower in the latter group 12 months after the start of chemotherapy.     

The effects of long term fadrozole hydrochloride treatment in patients with advanced stage breast cancer

Fadrozole hydrochloride at a dose of 2 mg b.i.d. has been shown to be an effective aromatase inhibitor in advanced stage breast cancer patients as determined by its ability to significantly suppress endogenous estrogen biosynthesis over a 12-week period. Continued suppression of circulating estrogen levels over a prolonged period has not yet been examined in published reports. In this study, we report the extended use of fadrozole hydrochloride at a maintenance dose of 2 mg b.i.d. in a cohort of 11 patients extending to 973 days of therapy. Results show that the degree of suppression of plasma and urinary estrogens was maintained in all patients throughout the extended period of drug use. Continued estradiol suppression of over 50% or greater from baseline was observed, as was continued suppression of estrone to over 80% from baseline. Cortisol determinations after 9 months of treatment showed no suppression from baseline. The aldosterone values and responses to cortrosyn stimulation continued to be suppressed as first noted following the initial 3 months of the core clinical trial. Objective tumor response noted in the core clinical trial did not change until disease progression. The findings suggest that fadrozole hydrochloride maintains its ability to suppress the aromatase enzyme during long term use. No observable escape from suppression of plasma and urinary estrogens occurred during prolonged treatment.