The role of carboplatin in combination with paclitaxel in patients with castration-resistant prostate cancer.

Background: The aim of the present study was to examine the efficacy of carboplatin in combination with paclitaxel in patients with metastatic castration-resistant prostate cancer pretreated with multiple regimens including docetaxel and androgen receptor-targeted agents. Methods: Clinical data from patients treated with carboplatin plus paclitaxel were collected retrospectively from a single institution. Results: 43 patients with metastatic castration-resistant prostate cancer were identified. Median number of cycles was ten (range: 1 to 23), prostate-specific antigen response was observed in 18 (42%) patients, median progression-free survival was 115 days and median overall survival was 8.1 months. Conclusion: Combination chemotherapy using taxane with carboplatin is an effective and well-tolerated therapy in heavily pretreated patients with metastatic castration-resistant prostate cancer.

The prognosis of metastatic castration-resistant prostate cancer (mCRPC) refractory to docetaxel is poor, with only limited guidance on the optimal treatment strategy. We reviewed patients with mCRPC treated with weekly carboplatin/paclitaxel in a single institution, analyzing their prostate-specific antigen (PSA) response, progression-free survival, treatment duration and overall survival (OS). Potential predictive biomarkers and tolerability were evaluated. 43 patients treated between 2012 and 2020 were identified, including 40 refractory to docetaxel. 19 (44%) had received two prior chemotherapy regimens and 38 (88%) were pretreated with androgen receptor-targeted agents; 18 patients (42%) had bone-only disease and 16 (37%) had visceral disease. Median number of cycles was ten (range: 1 to 23), PSA response (>50% decline) was observed in 18 patients (42%), median progression-free survival was 115 days and median OS was 8.36 months. 11 patients (26%) experienced reversible grade 3 or 4 toxicity, two (5%) had febrile neutropenia, and no lethal adverse events were observed. The prognostic role for OS was confirmed for PSA response, higher line of therapy, pretreatment with enzalutamide, longer response to androgen-deprivation therapy and response to docetaxel. In conclusion, combination chemotherapy with carboplatin/paclitaxel is a viable, effective and well-tolerated therapy in heavily pretreated patients with mCRPC, but should be validated in a prospective trial.

Pembrolizumab plus axitinib combination and the paradigm change in the treatment of advanced renal cell carcinoma.

Sequential administration of single targeted agents has been challenged as the dominant treatment paradigm in patients with metastatic renal cell carcinoma by improved outcomes obtained with combination regimens based on immune checkpoint inhibitors. Most patients treated with sequential monotherapy eventually develop drug resistance and succumb to progressive disease, leading to the search for therapies that would overcome drug resistance and result in a more durable treatment response. Improved outcomes have been demonstrated in Phase III trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab and ipilimumab plus nivolumab. A statistically significant improvement of both progression-free and overall survival has been demonstrated for the axitinib plus pembrolizumab combination.

Intestinal permeability in patients with metastatic colon cancer treated with patupilone.

BACKGROUND: Only a limited number of cytotoxic drugs have shown activity in metastatic colorectal carcinoma. Patupilone is a novel agent with promising activity in this common cancer. Diarrhea represents the dose-limiting toxicity of patupilone. Measurement of intestinal permeability is one of the potential methods of non-invasive laboratory assessment of gastrointestinal toxicity. METHODS: We have assessed intestinal permeability by measuring absorption of lactulose, mannitol and xylose in 27 previously treated patients with metastatic colorectal cancer enrolled in a phase I trial of patupilone. RESULTS: Lactulose/mannitol and lactulose/xylose ratios increased after the treatment. Significantly higher lactulose/mannitol ratio was observed in patients who had severe diarrhea. Moreover, patients who subsequently had an adverse event of grade 3 or higher had significantly higher baseline lactulose/mannitol or lactulose/xylose ratios. CONCLUSIONS: Measurement of intestinal permeability using the lactulose/mannitol test may represent a biomarker for the monitoring, or even prediction of toxicity of cytotoxic drugs, including patupilone.

Pembrolizumab plus axitinib for the treatment of advanced renal cell carcinoma.

Introduction: The dominant paradigm of sequential therapy of metastatic renal cell carcinoma (mRCC) with single agents has recently been challenged by improved outcomes obtained with combined regimens with immune checkpoint inhibitors. These combined regimens include the combination of pembrolizumab plus axitinib.Areas covered: Here, we provide a brief overview of the current clinical data on the pembrolizumab plus axitinib combination including mechanism of action, pharmacokinetics, efficacy and safety profile.Expert opinion: Both agents targeting the vascular endothelial growth factor (VEGF) pathway and immune checkpoint inhibitors are active as single agents in mRCC. Improved outcomes have been demonstrated in phase 3 trials in comparison with sunitinib for the combinations of axitinib plus pembrolizumab, axitinib plus avelumab, bevacizumab plus atezolizumab, and ipilimumab plus nivolumab. Among these combinations, an OS benefit has, so far, demonstrated only for the combinations of axitinib with pembrolizumab and ipilimumab with nivolumab. Although there are currently no prospective data comparing the combination of ipilimumab and nivolumab with the combination of immune checkpoint inhibitors and VEGF inhibitors, currently available retrospective analyses indicate that these two approaches achieve comparable outcomes.

Prolonged treatment planning can increase real rectal dose in 3D brachytherapy for cervical cancer.

PURPOSE: The purpose of this study was to evaluate the influence of 3D brachytherapy planning time on the real dose distribution. MATERIAL AND METHODS: 10 patients with cervical cancer were evaluated using 2 computed tomography (CT) scans brachytherapy. The first scan was performed after the insertion of UVAG applicators, and the second was done after creating the treatment plan, just before the irradiation of first and third fraction. Both plans were compared in terms of changes of volumes and differences in the dose for high-risk organs using GEC-ESTRO Working Group parameters. RESULTS: The median planning time was 54 minutes (36-64 minutes). The absolute median change of volume for bladder, rectum, and sigmoid was 32.1 cm3 (1.6-108.6 cm3), 5.6 cm3 (0.4-61.8 cm3), and 8.4 cm3 (0.2-74.1 cm3), respectively. This difference led to an increased dose for bladder and sigmoid for D0.1cc by 46.7 cGy and 25.7 cGy, for D1cc by 59.2 cGy and 11.8 cGy, and for D2cc by 44.7 cGy and 10 cGy, respectively, per each fraction. Measured volume change in case of rectum led to a decreased dose per each fraction for D0.1cc with 7.1 cGy, for D1cc with 3.5 cGy, and for D2cc with 4.8 cGy. We observed that statistically significant dependency between the planning time and the dose was proved for rectum. The longer time for planning, the higher dose for rectum. The correlation coefficient for D0.1cc was 0.6715 (p = 0.0061), for D1cc was 0.6404 (p = 0.011), and for D2cc was 0.5891 (p = 0.0197). CONCLUSIONS: Extended treatment planning time for brachytherapy due to the changes in topography of small pelvis can lead to different dose in high-risk organs than previously planned. It seems that the most significant changes are related to rectum.

Lenvatinib for the treatment of kidney cancer.

INTRODUCTION: Sequential administration of single targeted agents has evolved as the dominant paradigm in advanced RCC treatment. Lenvatinib plus everolimus is the first combination therapy in advanced RCC to show improvement in efficacy compared to monotherapy in advanced RCC while maintaining manageable toxicity profile. Areas covered: This review gives a brief overview of the contemporary clinical data on lenvatinib including its mechanism of action, pharmacokinetics, efficacy and safety profile in combination with everolimus. The clinical applications of lenvatinib in combination with everolimus are addressed within the context of the current competitive therapeutic landscape of RCC. Expert commentary: Lenvatinib is a new VEGF receptor-targeted tyrosine kinase inhibitor approved in combination with everolimus for second-line therapy in patients with advanced renal cell carcinoma progressing on a first-line VEGF receptor-targeted tyrosine kinase inhibitor. The combination of lenvatinib with everolimus significantly improved progression-free survival compared with everolimus with a hazard ratio of 0.40 and increased objective response to 43%. Optimal sequence of therapy targeting the tumor and the immune system remains a challenge and further investigation is warranted.

Safety of mTOR inhibitors in breast cancer.

INTRODUCTION: Despite advances in the treatment of metastatic breast cancer, the lack of response or relapse/progression during the course of therapy continue to present a challenge towards deeper understanding of dysregulated signaling pathways in breast cancer. Consequently, there is an unmet medical need for the development of new agents to overcome the resistance to therapy and improve the treatment outcome. AREAS COVERED: In this review, the mechanism of action and the role of intracellular PI3K/AKT/mTOR signaling pathway inhibition in breast cancer patients are described. Everolimus has been approved in combination with exemestane for the treatment of hormone-receptor-positive advanced breast cancer after failure of nonsteroidal aromatase inhibitor therapy. The aim of this paper is to focus on the safety and efficacy of mTOR inhibitors in the treatment of breast cancer. Current strategies of major adverse event management and prevention are delineated. EXPERT OPINION: Study results demonstrate clearly that the inhibition of the PI3K/AKT/mTOR pathway represents a promising approach to improve the efficacy of other targeted therapies in estrogen receptor-positive breast cancer patients with an acceptable safety profile. Although side effects are not uncommon, these are usually mild to moderate in severity and manageable with supportive care and dose adjustments.

Role of subcutaneous formulation of trastuzumab in the treatment of patients with HER2-positive breast cancer.

Tumors in about 15% of patients with breast cancer overexpress HER2. Trastuzumab (Herceptin(®); F. Hoffmann-La Roche, Basel, Switzerland) is a humanized monoclonal antibody against HER2. While the introduction of trastuzumab has changed the natural course of HER2-positive breast cancer, the need for repeated administration of the drug over a prolonged period of time represents a challenge. Similarly to other chronic disorders, subcutaneous administration of monoclonal antibodies may be of advantage in this setting. The results of a prospective randomized Phase III study have demonstrated that subcutaneous trastuzumab is noninferior compared with the intravenous administration of the drug in terms of efficacy (assessed as pathological complete response rate) as well as in pharmacokinetic parameters. Moreover, another prospective randomized study showed that an overwhelming majority of patients prefer subcutaneous over intravenous trastuzumab. The advent of subcutaneous trastuzumab represents an important progress in the concept of cancer management that is based also on patient choice and preferences.

Predictive and prognostic significance of tumor-infiltrating lymphocytes in patients with breast cancer treated with neoadjuvant systemic therapy.

Despite the progress of tailored therapeutic strategies in patients with breast cancer, there is an unmet medical need for additional biomarkers that would guide therapy, including the administration of targeted agents. It has been demonstrated that the presence of tumor-infiltrating lymphocytes (TILs) is associated with prognosis in patients with early breast cancer. Moreover, TIL counts were shown to predict outcome of neoadjuvant chemotherapy. The neoadjuvant setting is increasingly used to assess the efficacy of new systemic therapies, and TILs are promising as a biomarker reflecting the immune response to tumor. Future studies should investigate on the integration of TILs as predictive biomarkers in patients treated with targeted- agents.

Bevacizumab in combination with IFN-α in metastatic renal cell carcinoma: the AVOREN trial.

Metastatic renal cell carcinoma (mRCC) is tumor resistant to all cytotoxic agents. During the last decade, effective targeted therapies emerged including sunitinib, pazopanib and the combination of bevacizumab with IFN-α. The use of bevacizumab plus IFN-α combination in mRCC is supported by the AVOREN trial. Although the primary end point of the AVOREN trial was overall survival, progression-free survival was used to evaluate efficacy and served as the basis of regulatory submission owing to the advent of targeted agents that probably resulted in the prolongation of overall survival in both experimental and control arms. The doubling of median progression-free survival in the AVOREN trials (from 5.4 to 10.2 months) is remarkably similar compared with the results of Phase III trials with sunitinib and pazopanib. Bevacizumab plus IFN-α is the only combined regimen currently used in mRCC and serves as a comparator in the trials combining bevacizumab with other agents.