The skeleton is the target tissue for many types of tumors, and, recently, the survival of patients with prostate cancer metastasis has been increased using α-emitting drugs known as targeted α ...therapies. The use of α-radiopharmaceuticals in medicine was hypothesized at the beginning of the nineteenth century after the observation that α-radionuclides were associated with high cell-killing energy and low tissue penetration in healthy tissues. In the prostate cancer (PC) scenario, current research suggests that this class of radiopharmaceuticals has limited toxicity, and that the mechanism of action does not overlap with pre-existing drugs, allowing us to extend therapeutic armaments and address medical oncology towards personalized and precision medicine. Ongoing studies may extend these benefits also to bone metastases deriving from other neoplasms. The aim of this review is to summarize the current research on targeted α therapies and try to identify the right patient to be treated in the right time in order to integrate in these medications in the every-day clinical practice.
Purpose
Agents targeting HR-positive, HER2-negative locally advanced or metastatic breast cancer have improved patient outcomes compared with conventional single-agent endocrine therapy. Currently, ...approved targeted agents include everolimus and three CDK4/6 inhibitors, palbociclib, ribociclib, and abemaciclib. Unlike the well-characterized and easily manageable safety profile of endocrine therapies, adverse events associated with targeted therapies are complex and potentially severe. Their prompt recognition and treatment, crucial for prolonged endocrine sensitivity and survival, may be challenging and requires a multidisciplinary effort and a good knowledge of drug interactions.
Methods
We reviewed the current evidence on the drug safety of targeted agents for metastatic breast cancer currently used in clinical practice in Italy, supported by the clinical experience of Italian oncologists with expertise in the field.
Results
All oncologists had used CDK4/6 inhibitors in clinical practice and/or within a clinical trial. The clinical management of toxicities, including dose adjustments, treatment interruptions, and concerns regarding special populations is discussed, and the management of relevant adverse events, related to individual agents and class-specific, toxicities is reviewed. Hematologic toxicities have the greatest impact on clinical management of the disease and on patients. Although toxicities associated with the new treatments result in more visits to the physician and more time and attention with patients, they are manageable, with no need for the oncologist to consult with specialist physicians.
Conclusions
Based on the available evidence and current guidelines, we propose a series of practical recommendations for multidisciplinary clinical management of the various toxicities associated with the addition of targeted agents to endocrine therapy.
Immune Checkpoint Inhibitors (ICIs) lead to durable response and a significant increase in long-term survival in patients with advanced malignant melanoma (MM) and Non-Small Cell Lung Cancer (NSCLC). ...The identification of serum cytokines that can predict their activity and efficacy, and their sex interaction, could improve treatment personalization.
In this prospective study, we enrolled immunotherapy-naïve patients affected by advanced MM and NSCLC treated with ICIs. The primary endpoint was to dissect the potential sex correlations between serum cytokines (IL-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, GM-CSF, MCP-1, TNF-ɑ, IP-10, VEGF, sPD-L1) and the objective response rate (ORR). Secondly, we analyzed biomarker changes during treatment related to ORR, disease control rate (DCR), progression free survival (PFS) and overall survival (OS). Blood samples, collected at baseline and during treatment until disease progression (PD) or up to 2 years, were analyzed using Luminex xMAP or ELLA technologies.
Serum samples from 161 patients (98 males/63 females; 92 MM/69 NSCLC) were analyzed for treatment response. At baseline, IL-6 was significantly lower in females (F) versus males (M); lower levels of IL-4 in F and of IL-6 in both sexes significantly correlated with a better ORR, while higher IL-4 and TNF-ɑ values were predictive of a lower ORR in F versus M. One hundred and sixty-five patients were evaluable for survival analysis: at multiple Cox regression, an increased risk of PD was observed in F with higher baseline values of IL-4, sPD-L1 and IL-10, while higher IL-6 was a negative predictor in males. In males, higher levels of GM-CSF predict a longer survival, whereas higher IL-1β predicts a shorter survival. Regardless of sex, high baseline IL-8 values were associated with an increased risk of both PD and death, and high IL-6 levels only with shorter OS.
Serum IL-1β, IL-4, IL-6, IL-10, GM-CSF, TNF-ɑ, and sPD-L1 had a significant sex-related predictive impact on ORR, PFS and OS in melanoma and NSCLC patients treated with ICIs. These results will potentially pave the way for new ICI combinations, designed according to baseline and early changes of these cytokines and stratified by sex.
Purpose
Anticancer treatment-related toxicities can impact morbidity and mortality, hamper the administration of treatment, worsen the quality of life and increase the burden on the healthcare ...system. Therefore, their prompt identification is crucial. NICSO (Italian Network for Supportive Care in Cancer) conducted a nationwide randomized trial to evaluate the role of a planned, weekly phone-based nurse monitoring intervention to prevent and treat chemotherapy, targeted therapy- and immunotherapy-related toxicities. Here, we report the results from the chemotherapy arm.
Methods
This was a nationwide, randomized, open-label trial conducted among 29 Italian centers (NCT04726020) involving adult patients with breast, colon, or lung cancer and a life expectancy ≥6 months receiving adjuvant chemotherapy. Patients received either a weekly nurse monitoring phone call and an educational leaflet reporting practical advice about prevention and treatment of toxicities (experimental group) or the educational leaflet only (control group).
Results
The addition of a nurse monitoring intervention may help reduce time spent with severe toxicities (grade ≥3), particularly those less frequently reported in clinical practice, such as fatigue. When considering grade 1–2 AEs, times with mild/moderate diarrhea, mucositis, fatigue and pain were shorter in the experimental arm. Time spent without AEs was significantly longer in the experimental arms for all the toxicities. The requirement for special medical attention was comparable between groups.
Conclusion
This study suggests the need for implementing a better system of toxicity assessment and management for patients treated with adjuvant chemotherapy to promote effective preventive and/or therapeutic intervention against these events.
Background
Angiogenesis has been recognized as the most important factor for tumor invasion, proliferation, and progression in metastatic renal cell carcinoma (mRCC). However, few clinical data are ...available regarding the efficacy of cabozantinib following immunotherapy.
Objective
To describe the outcome of cabozantinib in patients previously treated with immunotherapy.
Patients and methods
Patients with mRCC who received cabozantinib immediately after nivolumab were included. The primary endpoint was to assess the outcome in terms of efficacy and activity.
Results
Eighty-four mRCC patients met the criteria to be included in the final analysis. After a median follow-up of 9.4 months, median overall survival was 17.3 months. According to the IMDC criteria, the rates of patients alive at 12 months in the good, intermediate, and poor prognostic groups were 100%, 74%, and 33%, respectively (
p
< 0.001). The median progression-free survival (PFS) was 11.5 months (95% CI 8.3–14.7); no difference was found based on duration of previous first-line therapy or nivolumab PFS. The overall response rate was 52%, stable disease was found as the best response in 25.3% and progressive disease in 22.7% of patients. Among the 35 patients with progressive disease on nivolumab, 26 (74.3%) patients showed complete/partial response or stable disease with cabozantinib as best response after nivolumab. The major limitations of this study are the retrospective nature and the short follow-up.
Conclusions
Cabozantinib was shown to be effective and active in patients previously receiving immune checkpoint inhibitors. Therefore, cabozantinib can be considered a valid therapeutic option for previously treated mRCC patients, irrespective of the type and duration of prior therapies.
Abstract Introduction Pazopanib is a standard first line treatment for metastatic clear-cell renal cell carcinoma (ccRCC). Very few data on its activity in non-clear cell RCC (nccRCC) are currently ...available. The aim of this study was to retrospectively analyze efficacy and toxicity of pazopanib in nccRCC patients. Patients and Methods Records from advanced nccRCC patients (consecutive sample) treated with first line pazopanib between 2010 and 2015 at 17 Italian centers were reviewed. Response rate (RR), progression free survival (PFS), and overall survival (OS) were evaluated. Univariate and descriptive analyses were performed. Results 37 patients with nccRCC were treated with first line pazopanib. 51% had papillary histology, 24% chromophobe, 22% unclassified and 3% had Xp11.2 translocation. Dose reductions/temporary interruptions for toxicity were required in 46% of cases. G3-4 toxicity was seen in 32%, G1-2 in 89% of cases. 81% achieved disease control, with 10 partial responses (27%) and 20 cases of stable disease (54%); 16% of patients had disease progression as best response. Median PFS and OS were 15.9 and 17.3 months respectively. At the univariate analysis, nephrectomy ( p =0.020), MSKCC score ( p <0.001), basal neutrophil/lymphocyte ratio (NLR) ( p =0.009) and performance status (PS) ( p =0.001) were associated with PFS; MSKCC score ( p <0.001), IMDC score ( p =0.003), PS ( p <0.0001), nephrectomy ( p =0.002), histology ( p =0.035), dose reductions/interruptions ( p =0.039), best response to treatment ( p <0.001) and NLR ( p =0.008) were associated with OS. Conclusions In nccRCC patients, treatment with pazopanib was effective and feasible; dose reductions required for toxicity were similar as expected in ccRCC.
Learning Objectives
After completing this course, the reader will be able to:
Compare the use of i.t. therapy and systemic therapies for patients with neoplastic meningitis.
Describe new drugs ...showing promise for neoplastic meningitis.
This article is available for continuing medical education credit at CME.TheOncologist.com
Neoplastic meningitis is a result of the spread of malignant cells to the leptomeninges and subarachnoid space and their dissemination within the cerebrospinal fluid. This event occurs in 4%–15% of all patients with solid tumors and represents an important prognostic factor for poor survival. Neoplastic meningitis should be diagnosed in the early stages of disease to prevent important neurological deficits and to provide the most appropriate treatment. Despite new diagnostic approaches developed in recent years, such as positron emission tomography–computed tomography and new biological markers, the combination of magnetic resonance imaging without and with gadolinium enhancement and cytology still has the greatest diagnostic sensitivity.
Recently, no new randomized studies comparing intrathecal (i.t.) with systemic treatment have been performed, yet there have been a few small phase II studies and case reports about new molecularly targeted substances whose successful i.t. or systemic application has been reported. Trastuzumab, gefitinib, and sorafenib are examples of possible future treatments for neoplastic meningitis, in order to better individualize therapy thus allowing better outcomes.
In this review, we analyze the most recent and interesting developments on diagnostic and therapeutic approaches.
摘要
癌性脑膜炎是恶性细胞扩散至软脑膜和蛛网膜下腔及其在脑脊液播散所致。癌性脑膜炎在实体瘤患者中的发生率为4%~15%，它是生存不佳的重要预后因素。癌性脑膜炎应在疾病早期予以诊断，以便于预防患者发生重要的神经功能缺损，并给予患者最适当的治疗。尽管近年来已经开发了新的诊断方法，例如正电子发射计算机断层扫描和新的生物学标志物，但是磁共振成像（有和无钆增强）联合细胞学仍然是敏感性最强的诊断方法。
近期没有新的比较鞘内注射（i.t.）与全身治疗的随机研究，但仍有少数小样本II期研究和病例报告报道新型分子靶向物质的i.t.或全身用药获得成功。曲妥珠单抗、吉非替尼和索拉非尼是癌性脑膜炎未来可能疗法的实例，旨在改善个体化治疗，进而改善转归。
本综述分析诊断和治疗方法上最新而有希望的进展。
The most recent and interesting developments on diagnostic and therapeutic approaches in the treatment of neoplastic meningitis from solid tumors are reviewed.
AIM, PATIENTS & METHODS: To evaluate the real-world setting use of sunitinib, we reviewed data of our patients from January 2007 to December 2014.
In 114 patients, sunitinib was used as first-line ...TKI. Out of 110 evaluable patients, 5 complete responses, 37 partial responses, 42 stabilizations were reported. Median progression-free survival and overall survival (OS) were 14.3 and 28.4 months. Patients who received ≥ 4 full-dose cycles had a better OS (p = 0.02). A neutrophil-lymphocyte ratio <3 was associated both with OS and progression-free survival (50.4 vs 8.4 and 20.0 vs 3.3 months).
Sunitinib is active and feasible. Patients receiving <4 full-dose cycles or having increased neutrophil-lymphocyte ratio achieved worse outcomes: therefore, these are present potential predictive factors.
Background: There is pre-clinical evidence of synergism between cisplatin and temozolomide due to higher inhibition of O 6 -alkyl-guanine-alkyltransferase (AGAT), an enzyme involved in the mismatch ...repair system and in the mechanisms of drug resistance
to alkylating agents. Patients and Methods: Heavily pre-treated patients with temozolomide-refractory high-grade malignant
glioma received cisplatin at a dose of 75 mg/m 2 on day 1 and temozolomide at a dose of 150 mg/m 2 on days 1 to 5 every 21 days until progression or major toxicity. Results: Twenty-four patients were enrolled and a total
of 96 cycles were delivered (median for each patient=4). Toxicity was manageable and mostly grade 1-2: haematological, gastroenterological
(nausea and vomiting) and fatigue. In patients with glioblastoma, an overall response rate of 29.4% was achivied, with no
complete response, and with a disease control rate (responses plus stabilizations) of 64.7%. The median time to progression
was 3.8 months (95% confidence interval 2.4-6.8), progression-free survival at 6 months was 28% and overall survival was 7.0
months (95% confidence interval 4.8-11.0). Conclusion: The combination of temozolomide and cisplatin is safe and moderately
effective in the treatment of heavily pre-treated patients with relapsed high-grade glioma refractory to single-agent temozolomide.
In cancer patients, including women with a diagnosis of ovarian cancer, cancer antigen 125 (CA125) is used to evaluate the presence of peritoneal involvement. The aims of the present study were to ...assess CA125 reference intervals and reference change values (RCV) in postmenopausal reference women, postmenopausal women breast cancer free, reference men and cancer free men.
The series consisted of 433 subjects: 105 postmenopausal breast cancer free women and 56 cancer free men in addition to a total of 272 reference subjects (145 postmenopausal women and 127 men). Repeated CA125 measurements were made in a subset of 149 women and 54 men to calculate RCV and index of individuality. Serum CA125 levels were evaluated by a chemiluminescent assay.
In postmenopausal reference women, the mean CA125 value and 2.5th–97.5th percentiles were 6.70, 2.60–11.00 kU/L, respectively, with a unidirectional RCV of 38.4%. In postmenopausal breast cancer free women, the mean CA125 value and 2.5th–97.5th percentile were 7.45, 4.09–10.92 kU/L, respectively, with a RCV of 34.5%. The difference between the means was statistically significant (t=–3.02, p=0.003). In the two male subgroups, the difference between the means for CA125 was not statistically significant (t=0.43, p=0.665). On considering the entire male population, the mean CA125 value and 2.5th–97.5th percentiles were 7.50 and 2.40–13.2 kU/L, respectively, while the unidirectional RCV was 34.3%. In all the studied groups, the indices of individuality were equal to or below 0.6.
The extremely low index of individuality found underlines the importance of using the RCV instead of absolute values as a parameter when interpreting the CA125 data in the monitoring and follow-up of patients with ovarian cancer.
PDF
