Pembrolizumab (mAb to PD-1) has been recently approved for the therapy of pretreated urothelial cancer. Despite the efficacy, it is often accompanied by unpredictable and sometime severe ...immune-related (ir) adverse events (AEs). Here, we report the clinical and immune–biological characterization of a patient with a metastatic bladder cancer who developed myositis signs (M) and a myasthenia-like syndrome (MLS) during treatment with pembrolizumab. The patient presented an autoimmunity-associated HLA haplotype (HLA-A*02/HLA-B*08/HLA-C*07/HLA-DRB1*03) and experienced an increase in activated CD8 T-cells along the treatment. The symptomatology regressed after pembrolizumab discontinuation and a pyridostigmine and steroids-based therapy. This is the first report of concurrent M and MLS appearance in cancer patients receiving pembrolizumab. More efforts are needed to define early the risk and the clinical meaning of irAEs in this setting.
Background:
Real-world data on chemotherapy-naïve patients with metastatic castration-resistant prostate cancer (mCRPC) treated with abiraterone plus prednisone are limited, largely deriving from ...small retrospective studies.
Methods:
ABitude is an Italian, observational, prospective, multicenter study of mCRPC patients receiving abiraterone plus prednisone in clinical practice. Chemotherapy-naïve mCRPC patients were consecutively enrolled at abiraterone start (February 2016 to June 2017) and are being followed for 3 years, with evaluation approximately every 6 months. Several clinical and patients reported outcomes were examined.
Results:
In this second interim analysis, among 481 enrolled patients, 453 were evaluable for analyses. At baseline, the median age was 77 years and ~69% of patients had comorbidities (mainly cardiovascular diseases). Metastases were located mainly at bones and lymph nodes; 8.4% of patients had visceral metastases. During a median follow-up of 18 months, 1- and 2-year probability of radiographic progression-free survival were 73.9% and 56.2%, respectively; the corresponding rates for overall survival were 87.3% and 70.4%. In multivariable analyses, the number of bone metastases significantly affected radiographic progression-free survival and overall survival. During abiraterone plus prednisone treatment, 65% of patients had a ⩾50% prostate-specific antigen decline, and quality of life remained appreciably high. Among symptomatic patients according to the Brief Pain Inventory) (32%), scores significantly declined after 6 months of treatment. Overall, eight patients (1.7%) had serious adverse reactions to abiraterone.
Conclusions:
Abiraterone plus prednisone is effective and safe for chemotherapy-naïve mCRPC patients in clinical practice.
Background: Capecitabine is considered the treatment of choice for anthracycline- and taxane-pretreated metastatic breast
cancer. Mitomycin C seems to improve the activity of capecitabine by ...up-regulation of thymidine phosphorylase. Patients and
Methods: Fifty-five women with metastatic breast cancer previously treated with anthracycline-taxane were treated with mitomycin
C 10 mg/m 2 on day 1 every six weeks and capecitabine 1000 mg/m 2 on days 2-15 every three weeks. Results: An overall response rate of 38% was found, consisting of 3 (5%) complete responses
(CR) and 18 (33%) partial responses (PR); 8 patients (14%) had a stable disease (SD) for more than 4 months. The combination
was well-tolerated, with the main toxicities being neutropenia, diarrhea and fatigue; other toxicities were of mild to moderate
intensity without impairment in the quality of life of the patients. Conclusion: Capecitabine is confirmed as the drug of
choice in the treatment of anthracycline- and taxane-pretreated metastatic breast cancer and its combination with mitomycin
appears to improve its efficacy.
Mucinous adenocarcinoma (MA) of colorectal cancer seems associated with reduced responsiveness to chemotherapy. The overexpression of markers of resistance to fluorouracil and oxaliplatin has ...recently been demonstrated. We revised the outcomes of metastatic MA of the colon treated with FOLFOX. From January 2002 to December 2009, we treated 198 patients with metastatic colon cancer, of which 21 (10·6%) had diagnosis of MA and were compared with 42 control patients with non-mucinous adenocarcinoma (NMA). In MA group, three patients 14%; inhibitory concentration 95: ±7·5% reached partial response, and in NMA group, two patients obtained complete response and 16 obtained partial response with an overall response rate of 43% (inhibitory concentration 95: ±7·6%) with a significant statistical difference (P = 0·027). Median progression-free survival for MA group was 4 months with respect to 8 months for NMA (P = 0·0001); regarding overall survival, we registered a median of 8 months with respect to 18 months for MA and NMA (P = 0·001). In multivariate analysis, MA histology, Eastern Cooperative Oncology Group performance status 2, more than two metastatic sites, and peritoneal metastatic involvement resulted in negative independent prognostic factors. Also in our study, MA is connected to poor prognosis and reduced activity of chemotherapy. In the absence of randomised studies, it may be convenient to analyse this subgroup of patients within the large trials carried out on colorectal cancer.
Background: No standard chemotherapy has been defined for metastatic breast cancer patients pretreated with anthracyclines
and taxanes. In preclinical studies, mitomycin C (MMC) and capecitabine ...showed a synergistic effect by up-regulation of thymidine
phosphorylase, and both drugs were active against breast cancer with a lack of overlapping toxicity, making their combination
a well-tolerated regimen. Patients and Methods: A dose-finding study was carried out in order to determine the maximum tolerable
dose of MMC combined with fixed-dose capecitabine and to describe the dose-limiting toxicities. Results: Twenty-one patients
were enrolled, with metastatic breast cancer pretreated at least with anthracyclines and taxanes (3 at dose level I, 15 at
dose level II, 3 at dose level III). At dose level III (MMC 12 mg/m 2 and capecitabine 1000 mg/m 2 days 2-15) dose-limiting toxicities were recorded in 2 patients (G4 thrombocytopenia, neutropenic fever, G4 neutropenia);
dose level II (MMC 10 mg/m 2 and capecitabine 1000 mg/m 2 days 2-15) was extended for a better safety evaluation. No severe toxicity was noted at this dose level, and therefore this
dose was recommend for the phase II study. With regard to activity, 4 partial responses and 2 stable diseases (28%) were recorded.
Conclusion: Our data show that the combination is feasible, well tolerated and active in this set of patients.
Background
The BALLET study was an open‐label, multicenter, expanded access study designed to allow treatment with everolimus plus exemestane in postmenopausal women with hormone receptor‐positive ...metastatic breast cancer progressed following prior endocrine therapy. A post hoc analysis to evaluate if previous chemotherapy in the metastatic setting affects the safety profile of the combination regimen of everolimus and exemestane was conducted on the Italian subset, as it represented the major part of the patients enrolled (54%).
Patients and Methods
One thousand one hundred and fifty‐one Italian patients were included in the present post hoc analysis, which focused on two sets of patients: patients who never received chemotherapy in the metastatic setting (36.1%) and patients who received at least one chemotherapy treatment in the metastatic setting (63.9%).
Results
One thousand one hundred and sixteen patients (97.0%) prematurely discontinued the study drug, and the main reasons reported were disease progression (39.1%), local reimbursement of everolimus (31.1%), and adverse events (AEs) (16.1%). The median duration of study treatment exposure was 139.5 days for exemestane and 135.0 days for everolimus. At least one AE was experienced by 92.5% of patients. The incidence of everolimus‐related AEs was higher (83.9%) when compared with those that occurred with exemestane (29.1%), and the most commonly reported everolimus‐related AE was stomatitis (51.3%). However, no significant difference in terms of safety related to the combination occurred between patients without and with chemotherapy in the metastatic setting.
Conclusion
Real‐life data of the Italian patients BALLET‐related cohort were an adequate setting to state that previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane.
Implications for Practice
With the advent of new targeted agents for advanced or metastatic breast cancer, multiple lines of therapy may be possible, and components of the combined regimens can overlap from one line to another. Thus, it is important to assess even the potential of cumulative and additive toxic effects among the drugs. Previous chemotherapy did not affect the safety profile of the combination regimen of everolimus and exemestane. The continuous monitoring of the safety signals of this drug combination from general clinical practice is important, in particular for stomatitis.
摘要
背景. BALLET研究是一项开放性、多中心、扩大供药研究, 患有激素受体阳性转移性乳腺癌且既往内分泌治疗后疾病进展的绝经后女性可在研究中接受依维莫司和依西美坦联合治疗。入组患者大部分为意大利人（54%）, 因此在意大利患者子集中进行了一项事后分析, 以评价既往在疾病转移后接受化疗是否会影响依维莫司和依西美坦联合治疗方案的安全性特征。
患者和方法. 本项事后分析纳入了1 151例意大利患者, 重点分析两组患者：从未接受过化疗的转移性乳腺癌患者（36.1%）和至少接受过一次化疗的转移性乳腺癌患者（63.9%）。
结果. 1 116例患者（97.0%）提前停用研究药物, 报告的主要原因为疾病进展（39.1%）、当地报销依维莫司（31.1%）和不良事件（AE；16.1%）。依西美坦和依维莫司的研究治疗中位持续时间分别为139.5天和135.0天。92.5%的患者至少发生1例AE。依维莫司（83.9%）相关AE的发生率高于依西美坦（29.1%）, 最常报告的依维莫司相关AE为口腔炎（51.3%）。然而, 接受和未接受化疗的转移性乳腺癌患者在联合治疗的相关安全性方面没有显著差异。
结论. BALLET研究中意大利患者队列的实际数据充分说明, 既往化疗不影响依维莫司和依西美坦联合治疗方案的安全性特征。
对临床实践的提示：晚期或转移性乳腺癌的新靶向药物问世后, 患者或许可以接受多线治疗, 而各线联合治疗方案中的药物可能相互重叠。因此, 评估药物毒性作用的潜在累积和叠加风险至关重要。既往化疗不影响依维莫司和依西美坦联合治疗方案的安全性特征。在一般临床实践中必须持续监测这一联合用药的安全性信号, 特别是口腔炎。
This study presents results of the BALLET study, which focused on the use of everolimus/exemestane combination in postmenopausal women with ER+ locally advanced or metastatic breast cancer after recurrence or progression after nonsteroidal aromatase inhibitor treatment. Real‐life data of the cohort are reported.
High-dose chemotherapy (HDC) with autologous hematopoietic progenitor cell transplantation (AHPCT) for high-risk (HR) or metastatic breast cancer (MBC) is no longer an option.
An expert panel ...including medical oncologists and hematologists produce an opinion paper on the use of HDC and AHPCT in BC patients and they explain why they believe that; despite inconclusive results thus far, this treatment should have an ongoing role in breast cancer management under clinical trials.
HDC with AHPCT has become a safe treatment modality and an advantage in disease-free survival has been observed in most of the studies with HDC, with the caveat that today, even a limited relapse-free survival and progression-free survival benefit is sufficient for the approval of new antineoplastic agents. Moreover, in HRBC, an overall survival benefit by HDC could be achieved in the HER2-ve and triple-negative populations and, in this setting, HDC with AHPCT represents a therapeutic option that can be proposed to well-informed patients. In MBC, the HDC approach should be investigated further in selected patients with HER2-ve, chemosensitive disease. This paper is not intended to give any conclusion, but rather to open a debate on the value of HDC in HR and MBC.
Aims and background
Metastatic colorectal cancer has a heterogeneous behavior, and a set of patients will have minimal response and rapid disease progression. To understand this heterogeneity, ...studies have evaluated biological and clinical prognostic factors. Alkaline phosphatase seems to be a key prognostic factor, so we have reviewed the outcomes of our patients with respect to alkaline phosphatase levels.
Methods and study design
Between January 2003 and December 2008, we treated with the FOLFOX 4 regimen 103 consecutive patients with metastatic colorectal cancer. Thirty-two patients had alkaline phosphatase ≥300 U/l.
Results
Median time to progression was 4 months for patients with high alkaline phosphatase levels and 8 months for those with low alkaline phosphatase levels. Median overall survival was 8 and 17.5 months, respectively. Only 3 patients in the high alkaline phosphatase group obtained partial response (9.4%) compared to 3 complete responses and 24 partial responses (41.5%) in low alkaline phosphatase group. Toxicity was substantially different, with more grade 3–4 neutropenia, diarrhea and oral mucositis in the high than low alkaline phosphatase group.
Conclusions
Alkaline phosphatase is an uncomplicated and potent prognostic factor. Patients with high alkaline phosphatase levels had a poor prognosis. Free full text available at www.tumorionline.it
Gastric cancer is often diagnosed in advanced stage (AGC) and in elderly patients. Current chemotherapies induce severe toxicity and are difficult to deliver. Some authors have shown the activity and ...safety of oxaliplatin with various 5-fluorouracil (FU) and leucovorin (LV) infusions in AGC. The aim of our study was to evaluate the feasibility of the FOLFOX-4 regimen in elderly patients with AGC. From 6/2003 to 7/2005, 33 patients (median age 74 years, range 66-79 years) were enrolled into the study. 31 patients were assessable for the safety analysis and for response. We recorded complete response in 4 patients (13%), partial response in 6 patients (19%), 9 (29%) stable disease and 12 progressive disease for an overall response rate of 32% (95% CI, 16% to 48%). At median follow-up of 20 months the median time to progression was 6.4 months. The therapy was well tolerated, the main G1/2 toxicities were nausea, vomiting and diarrhea. Only 2 patients suffered from severe vomiting. Severe hematologic toxicities were uncommon. Anemia G3 was recorded in 3 patients, neutropenia G3 in 6 patients and febrile neutropenia in 1 patient. G1 and G2 neurotoxicity were a common event while G3 sensorial neuropathy was not reported. We conclude that although our patients were elderly and most had a PS 2, the regimen was manageable, easy to deliver, well accepted by the patients and active.
To evaluate the role of chemotherapy combined with curative radiotherapy in breast cancer patients who presented with recurrent ipsilateral supraclavicular lymph node metastases (ISLM) without ..."nonregional disease," we designed an observational study performed prospectively.
Forty-four consecutive patients with ISLM from breast cancer as part of recurrent regional disease without distant metastases were included in this study. All patients received chemotherapy with doxorubicin-based schema or paclitaxel for six courses and curative radiotherapy (60 Gy/30 fractions of 2 Gy/5 days a week). An "involved field" radiation was delivered during the interval between the third and fourth chemotherapy course; hormonal therapy was given based on receptor status.
The rate of overall clinical response after chemotherapy and radiotherapy was 94.9%. Median time to progression and overall survival were 28 and 40 months, respectively; the 5-year actuarial overall survival and disease-free survival rates were 35% (95% confidence interval, 19-51) and 20% (95% confidence interval, 6-34), respectively.
A curative course of intravenous chemotherapy and radical irradiation is feasible in patients with ISLM. All patients presenting recurrence in supraclavicular nodes should be treated with definitive locoregional treatments and systemic therapy because the outcomes are better than might be historically assumed.
PDF
