一种新型《乳腺癌治疗相关心血管毒性临床评分表》的价值分析

背景与目的:乳腺癌治疗相关心血管疾病已成为乳腺癌患者死亡的原因之一,为协助临床肿瘤科医师对患者的心血管疾病风险因素进行筛查,复旦大学附属中山医院肿瘤心脏病学团队拟定《乳腺癌治疗相关心血管毒性临床评分表》,协助临床医师对乳腺癌非手术患者进行评估,并采用该评分表对复旦大学附属中山医院的乳腺癌患者进行回顾性分析.方法:本研究...     

Inflammatory breast cancer: clinical course, diagnosis and treatment

To identify influence of different therapeutic and prognostic factors on survival, a review of the data on treatment of 197 patients with inflammatory breast cancer was carried out at the Dispensary (1994-2004). Multimodal treatment included combinations of radiotherapy, mastectomy and chemotherapy (CMF--75; CAF--98 and taxanes--9). Significantly lower survival was reported for patients with lymph node involvement (N1, N2 and N3) and those without mastectomy and radiotherapy. Overall 10-year survival was registered only in those who had received chemotherapy, radiotherapy and mastectomy (20.2% +/- 5.5); overall 5-year survival was 42.0% +/- 4.8.     

The clinical course and treatment results of patients with postresection locally recurrent lung cancer.

Of 1018 patients with lung cancer seen in the division of radiation therapy between 1963 and 1976, forty-six patients (4.5%) presented with postresection local recurrence and no documented distant metastasis. The median time to recurrence was thirteen months. Most patients had central recurrence with hilar or mediastinal lymph node metastasis, parenchymal consolidation, main stem nodule or bronchial stump tumor. There was a propensity for these tumors to remain limited to the site of origin. Death was most often from local/regional disease rather than distant metastasis. In this clinical setting the effectiveness of radiotherapy was observed in terms of palliation and improved survival. Strong determinants to survival were cell type, tumor dose and tumor response. The median survival was eleven months.     

THE CLINICAL COURSE AND TREATMENT RESULTS OF LUNG METASTASES FROM BREAST CANCER

Ａｐｐｒｏｘｉｍａｔｅｌｙ３０％ｏｆｐａｔｉｅｎｔｓｗｉｔｈｂｒｅａｓｔｃａｎｃｅｒｈａｖｅｒｅｃｕｒｅｎｃｅｏｆｄｉｓｅａｓｅａｎｄｍｅｔａｓｔａｓｅｓｗｉｔｈｉｎ５ｙｅａｒｓａｆｔｅｒｏｐｅｒａｔｉｏｎｏｎｐｒｉｍａｒｙｔｕｍｏｒ，ｗｉｔｈａｒｅ...     

乳腺癌肺转移的临床病程及治疗研究

目的探讨乳腺癌肺转移的临床病程特点与内科治疗结果。方法共收治１２２例乳腺癌肺转移患者。全部患者均行化疗或内分泌治疗,疗效评价按ＷＨＯ标准,生存率按寿命表法计算。结果原发癌初次治疗后出现肺转移的中位时间为２２个月,继发转移部位以肺内、肝、骨多见。治疗总有效率为４８％,其中ＣＲ率１５％。含ＤＤＰ方案的ＣＲ率（２１％）高于非ＤＤＰ方案（７％,Ｐ＜０．０５）,接受前者治疗的患者中位生存期比后者长;含蒽环类药方案的ＰＲ率（４８％）高于非蒽环类方案（２０％,Ｐ＜０．００１）,但两组患者的中位生存期相近;而化疗与化疗加内分泌治疗的ＣＲ与ＰＲ率差异无显著意义（Ｐ＞０．０５）。本组患者１,３,５和１０年生存率分别为７７％、２２％、１１％和１０％。影响生存期的因素包括近期疗效、原发肿瘤大小、无病间隙期、肺转移数目、是否合并其他部位转移等。结论本研究确定了乳腺癌肺转移的临床病程特征及预后因素。联合化疗特别是含ＤＤＰ的方案可能延长患者的生存期。     

Twelfth Aspen cancer conference: Mechanisms of toxicity and carcinogenesis

This article is a US Government work and, as such, is in the public domain in the United States of America.     

Mechanisms of radiation-induced brain toxicity and implications for future clinical trials

Radiation therapy is widely used in the treatment of primary malignant brain tumors and metastatic tumors of the brain with either curative or palliative intent. The limitation of cancer radiation therapy does not derive from the inability to ablate tumor, but rather to do so without excessively damaging the patient. Among the varieties of radiation-induced brain toxicities, it is the late delayed effects that lead to severe and irreversible neurological consequences. Following radiation exposure, late delayed effects within the CNS have been attributable to both parenchymal and vascular damage involving oligodendrocytes, neural progenitors, and endothelial cells. These reflect a dynamic process involving radiation-induced death of target cells and subsequent secondary reactive neuroinflammatory processes that are believed to lead to selective cell loss, tissue damage, and functional deficits. The progressive, late delayed damage to the brain after high-dose radiation is thought to be caused by radiation-induced long-lived free radicals, reactive oxygen species, and pro-inflammatory cytokines. Experimental studies suggest that radiation-induced brain injury can be successfully mitigated and treated with several well established drugs in wide clinical use which exert their effects by blocking pro-inflammatory cytokines and reactive oxygen species. This review highlights preclinical and early clinical data that are translatable for future clinical trials.     

Phase I clinical trial of alitretinoin and tamoxifen in breast cancer patients: toxicity, pharmacokinetic, and biomarker evaluations.

PURPOSE: To determine the overall and dose-limiting toxicities (DLTs) of alitretinoin (9-cis-retinoic acid) in combination with tamoxifen and the pharmacokinetics of alitretinoin alone and when combined with tamoxifen in patients with metastatic breast cancer. The effect of tamoxifen and alitretinoin on MIB-1, a marker of proliferation, in unaffected breast tissue was explored. PATIENTS AND METHODS: Eligible patients had metastatic breast cancer. Previous tamoxifen therapy was allowed. Planned dose levels for alitretinoin ranged from 50 to 140 mg/m2/d with 20 mg/d tamoxifen in all patients after 4 weeks of alitretinoin as a single agent. Plasma concentrations of alitretinoin and retinol were measured at baseline and after 1, 2, and 3 months. Breast core biopsies were obtained at baseline and after 2 months of therapy. RESULTS: Twelve patients with metastatic breast cancer received a total of 86 cycles of therapy. At 90 mg/m2/d, three of five patients experienced a DLT: grade 3 headache, grade 3 hypercalcemia, and grade 3 noncardiogenic pulmonary edema. At 70 mg/m2/d, one of six patients experienced a DLT (headache), and this level was considered the maximal tolerated dose in this study. Three toxicities occurred that had not been reported previously with alitretinoin: an asymptomatic delay in dark adaptation, a marked decrease in high-density lipoprotein cholesterol, and the occurrence of enthesopathy. Two of the nine assessable patients had a durable clinical response: one partial response and stable disease for 18 months and one complete response in continuous remission for 48+ months. Both responding patients were estrogen receptor-positive and had had previous tamoxifen therapy. There was a high degree of interpatient variability of plasma alitretinoin concentrations, although a significant decline in alitretinoin plasma levels over time was observed. MIB-1 scores declined in four of the eight paired breast specimens obtained. CONCLUSION: The combination of tamoxifen and alitretinoin is well tolerated and has antitumor activity in metastatic breast cancer. The recommended phase II dose is 70 mg/m2/d with 20 mg/d tamoxifen.     

组蛋白去乙酰化酶抑制剂在肿瘤研究中的机制及临床应用

组蛋白去乙酰化酶(HDAC)介导的可逆性组蛋白乙酰化对一系列生理进程及恶性肿瘤的调控产生重要影响.由于HDAC抑制剂(HDACi)可以促进肿瘤细胞凋亡而对正常细胞作用极小,使其已经发展成为一类新型的抗肿瘤药物,其中部分已进入临床试验阶段.HDACi中如伏立诺他及罗米地辛已经被FDA批准用于进展期、复发难治的皮肤T细胞淋巴瘤患者中.对HDAC药物作用机制的研究将有助于其深入临床应用.     

The clinical impacts of postoperative complications after colon cancer surgery for the clinical course of adjuvant treatment and survival

Aim

We investigated whether or not postoperative complications (POCs) themselves have a negative survival impact or indirectly worsen the survival due to insufficient adjuvant chemotherapy in a pooled analysis of two large phase III studies performed in Japan

Patients and methods

The study examined the patients who enrolled in 1304, phase III study comparing the efficacy of 6 and 12 months of capecitabine as adjuvant chemotherapy for stage III colon cancer patients and in 882, a phase III study to confirm the tolerability of oxaliplatin, fluorouracil, and l-leucovorin in Japanese stage II/III colon cancer patients. In our study, POCs were defined as the following major surgical complications: anastomotic leakage, pneumonia, bowel obstruction/ileus, surgical site infection, postoperative bleeding, urinary tract infection, and fistula. Patients were classified as those with POCs (C group) and those without POCs (NC group).

Results

A total of 2095 patients were examined in the present study. POCs were observed in 169 patients (8.1%). The overall survival (OS) rates at 5 years after surgery were 75.3% in the C group and 86.5% in the NC group (p = 0.0017). The hazard ratio of POCs for the OS in multivariate analysis was 1.70 (95% confidence interval, 1.19 to 2.45; p = 0.0040). The time to adjuvant treatment failure (TTF) of adjuvant chemotherapy was similar between the groups, being 68.6% in the C group and 67.1% in the NC group for the 6-month continuation rate of adjuvant chemotherapy. The dose reduction rate of adjuvant chemotherapy and adjuvant treatment suspension rate were also similar between the groups (C vs. NC groups: 45.0% vs. 48.7%, p = 0.3520; and 52.7% vs. 55.0%, p = 0.5522, respectively).

Conclusion

POCs were associated with a poor prognosis but did not affect the intensity of adjuvant chemotherapy. These results suggested that POCs themselves negatively influence the survival.

     

Hepatic toxicity resulting from cancer treatment

Radiation-induced liver disease (RILD), often called radiation hepatitis, is a syndrome characterized by the development of anicteric ascites approximately 2 weeks to 4 months after hepatic irradiation. There has been a renewed interest in hepatic irradiation because of two significant advances in cancer treatment: three dimensional radiation therapy treatment planning and bone marrow transplantation using total body irradiation. RILD resulting from liver radiation can usually be distinguished clinically from that resulting from the preparative regime associated with bone marrow transplantation. However, both syndromes demonstrate the same pathological lesion: veno-occlusive disease. Recent evidence suggests that elevated transforming growth factor β levels may play a role in the development of veno-occlusive disease. Three dimensional treatment planning offers the potential to determine the radiation dose and volume dependence of RILD, permitting the safe delivery of high doses of radiation to parts of the liver. The chief therapy for RILD is diuretics, although some advocate steroids for severe cases. The characteristics of RILD permit the development of a grading system modeled after the NCI Acute Common Toxicity Criteria, which incorporates standard criteria of hepatic dysfunction.     

临床Ⅰ期高龄非小细胞肺癌的治疗进展

随着人口的老龄化,高龄肺癌患者的比例在增大。近十几年来肺叶切除加纵隔淋巴结清扫一直是I期非小细胞肺癌(non small cell lung cancer,,NSCLC)患者的标准术式。近年研究发现Ⅰ期高龄NSCLC亚肺叶切除术可以取得和肺叶切除术相当的远期疗效而且可以保留更多的正常肺组织,有关Ⅰ期NSCLC的标准术式再次引起争议。Ⅰ期高龄NSCLC患者是一个特殊的群体,常因机体功能减退或合并有基础疾病而无法耐受开胸手术,胸腔镜的问世以及立体定向放射治疗技术的发展使患者有了更多的选择。Ⅰ期高龄NSCLC的治疗在朝着个体化和多样化方向发展     

A phase I study of interleukin-2 in children with cancer and evaluation of clinical and immunologic status during therapy. A Pediatric Oncology Group Study

The authors performed a Phase I study to assess the toxicity and hematologic effect of recombinant human interleukin-2 (rIL-2) in seven children with advanced malignancies. The rIL-2 was given as a bolus injection of 1 or 3 X 10(6) U/m2/dose three times a week (Monday, Wednesday, and Friday) for 3 weeks. No life-threatening toxicity occurred with the dose of 1 X 10(6) U/m2 of rIL-2. At a dose of 3 X 10(6) U/m2, therapy had to be terminated due to cardiovascular toxicity in two patients. Toxic effects at low-dose rIL-2 included fever, nausea, vomiting, and mild hypotension. High-dose rIL-2 toxicity included fluid retention, increased creatinine, oliguria, elevated liver enzymes, and significant hypotension. Immunologic studies showed that rIL-2 caused a drop in the number of circulating peripheral blood mononuclear cells, T-cells, and natural killer cells which returned to pretherapy levels or above by 24 to 48 hours. The rIL-2 exerted no growth or stimulatory activity on the leukemic cell population. To the authors' knowledge, this is the first report of a Phase I study of IL-2 therapy in children.     

Influence of sex on toxicity and treatment outcome in small-cell lung cancer.

PURPOSE: Female sex has been shown consistently to be a favorable prognostic factor in small-cell lung cancer (SCLC). Studies have shown that women with other tumor types experience greater treatment toxicity, but there have been few studies of sex-related toxicity in SCLC. PATIENTS AND METHODS: This was a sex-based retrospective analysis of four SCLC trials conducted by the National Cancer Institute of Canada Clinical Trials Group between 1987 and 1999. The 1,006 patients (648 males and 358 females) received similar chemotherapy consisting of cyclophosphamide-doxorubicin-vincristine and etoposide-cisplatin. Toxicities examined included myelosuppression, stomatitis, vomiting, and infection. Other end points included dose reductions and omissions, response, and survival. RESULTS: Women experienced significantly more hematologic toxicity than men (grade 3 and 4 anemia, 16.3% v 7.6%, respectively, P < .001; grade 3 and 4 leukopenia, 80.4% v 69.2%, respectively, P = .0001). However, toxic death rates were similar for men and women (1.5% v 1.1%, respectively, P = .58). Women also had significantly more stomatitis and vomiting of all grades. Despite increased toxicity, 76% of females versus 73.4% of males received all six treatment cycles (P = .38), but 52% of females versus 43.4% of males had treatment delayed for 2 weeks or more (P = .022). Only 31.8% of females and 28.2% of males had at least one cycle of chemotherapy dose reduction (P = .23). The overall response rate was 80.3% for females and 66.9% for males (P < .0001), and the median survival time was 1.31 years for females compared with only 0.91 year for males (P < .0001). CONCLUSION: Women experience more chemotherapy-related toxicity in the treatment of SCLC, but they also have increased response rates and survival.     

Cisplatin and novobiocin in the treatment of non-small cell lung cancer. A Southwest Oncology Group study.

Novobiocin, a commercially available oral antibiotic, inhibits DNA topoisomerase II in a manner shown in cell culture to enhance the cytotoxicity of alkylating agents and cisplatin. Thirty-six patients were entered on a Phase II trial using high-dose cisplatin (100 mg/m2 on days 1 and 8 for four cycles) after steady-state dosing with novobiocin (1000 mg or four 250-mg capsules every 12 hours for six doses, four of which were administered before each dose of cisplatin). One patient remains on study and cannot be evaluated for response. No complete responses were seen. Three patients (8%) had partial responses and an additional patient had an unconfirmed partial response. The median survival time of all patients was just less than 7 months. These results are comparable with those of other concurrent Southwest Oncology Group (SWOG) Phase II and III trials of high-dose cisplatin in non-small cell lung cancer (NSCLC). Novobiocin plasma levels were obtained for three patients and were approximately 50% of the optimal concentration as reported in cell culture for potentiation of cytotoxicity. It was concluded that an optimum test of novobiocin as a modulator of cytotoxicity may require the availability of an intravenous preparation.     

Intensity-modulated radiation therapy (IMRT) in the treatment of anal cancer: toxicity and clinical outcome

PURPOSE: To assess survival, local control, and toxicity of intensity modulated radiation therapy (IMRT) in squamous cell carcinoma of the anal canal. METHODS AND MATERIALS: Seventeen patients were treated with nine-field IMRT plans. Thirteen received concurrent 5-fluorouracil and mitomycin C, whereas 1 patient received 5-fluorouracil alone. Seven patients were planned with three-dimensional anteroposterior/posterior-anterior (AP/PA) fields for dosimetric comparison to IMRT. RESULTS: Compared with AP/PA, IMRT reduced the mean and threshold doses to small bowel, bladder, and genitalia. Treatment was well tolerated, with no Grade > or =3 acute nonhematologic toxicity. There were no treatment breaks attributable to gastrointestinal or skin toxicity. Of patients who received mitomycin C, 38% experienced Grade 4 hematologic toxicity. IMRT did not afford bone marrow sparing, possibly resulting from the clinical decision to prescribe 45 Gy to the whole pelvis in most patients, vs. the Radiation Therapy Oncology Group-recommended 30.6 Gy whole pelvic dose. Three of 17 patients, who did not achieve a complete response, proceeded to an abdominoperineal resection and colostomy. At a median follow-up of 20.3 months, there were no other local failures. Two-year overall survival, disease-free survival, and colostomy-free survival are: 91%, 65%, and 82% respectively. CONCLUSIONS: In this hypothesis-generating analysis, the acute toxicity and clinical outcome with IMRT in the treatment of anal cancer is encouraging. Compared with historical controls, local control is not compromised despite efforts to increase conformality and reduce normal structure dose.