Current Treatment Options in Oncology最新文献

Opinion statement: Pleural mesothelioma is an incurable cancer with unmet diagnostic and therapeutic needs. Due to its pattern of local spread, few patients are candidates for multimodality treatment and thus most patients only receive systemic therapy. Chemotherapy (pemetrexed plus platinum) was standard of care until the recent addition of immunotherapy (nivolumab plus ipilimumab, or pembrolizumab plus chemotherapy) as further first-line option. Physicians treating pleural mesothelioma should be aware of another option with Tumor Treating Fields (TTFields) therapy, a locoregionally-applied therapy utilizing electric fields generated by a portable medical device, and delivered to the tumor by skin-placed arrays. TTFields therapy delivered to the thorax using the NovoTTF- 100L device concomitant with pemetrexed and platinum agent is approved for unresectable pleural mesothelioma in the US, and received Conformité Européenne certification in Europe, based on results from the phase 2 STELLAR study (EF- 23; NCT02397928), where TTFields-related toxicity was limited to mild-to-moderate reversible skin reactions. Overall survival in the STELLAR study with TTFields therapy was 18.2 months, with further post-hoc analysis showing extended survival in patients with epithelioid histology. Within the evolving landscape of systemic treatments, TTFields therapy represents a novel and clinically versatile therapeutic option in the battle against pleural mesothelioma without introducing additional toxicities other than mild-to-moderate skin irritation. While promising, additional research is needed to optimize clinical application of TTFields therapy in patients with pleural mesothelioma, such as identifying the molecular determinants of therapy efficacy, and further investigation into the safe and effective delivery of TTFields therapy together with systemic agents, including immunotherapies.

Opinion statement: Sarcomas are rare neoplasms, whose complex management is a consequence of their heterogeneity. Due to their variegate histology and characteristics, prospective trials are challenging to design. Thus, diagnostic and therapeutic guidelines are often based on limited evidence available, and only few and dated systemic treatment regimens are included in our current practice. For all these reasons, we believe that implementing therapeutic options, including local approach, is mandatory to guarantee the best management possible to patients. We explored evidence about locoregional treatments, assuming they could represent a fundamental part of an integrated oncological approach. The goal is to maximize local control of oligometastatic or oligoprogressive diseases, saving systemic treatment options for later stages, as well as to avoid demolitive surgery in patients affected by locally advanced sarcomas. Although several retrospective and prospective series have been conducted, evidence available is still poor in our opinion. Research should focus on evaluating predictive factors and individualized follow up strategies to identify ideal patients' features and more sensitive histological subtypes.

Opinion statement: Budesonide is a potent topical glucocorticosteroid with limited systemic activity owing to its extensive hepatic first-pass metabolism following oral administration. Its efficacy and safety have been well-established in gastroenterology, particularly for inducing and maintaining remission in patients with inflammatory bowel diseases: mild-to-moderate ulcerative colitis, Crohn's disease and microscopic colitis. However, the potential role of oral budesonide in oncology has only recently been recognized, particularly for managing various types of gastrointestinal immune-related adverse events, which are among the most common toxicities observed in cancer patients treated with immune checkpoint inhibitors. Potential applications of oral budesonide in this context include the treatment of immunotherapy-induced microscopic and non-microscopic colitis, enteritis, upper gastrointestinal involvement, and, to a lesser extent, hepatitis. In these cases, oral budesonide may serve as a primary treatment to induce remission, replacing systemic steroids, or as a bridging therapy transitioning from systemic steroids, facilitating a quicker resumption of immunotherapy following its temporary discontinuation due to toxicity. Oral budesonide represents a particularly attractive treatment option in oncology due to its minimal systemic activity, low risk of steroid-related side effects, and very limited potential to cause immune suppression - offering a marked contrast to systemic steroids. In this article, we summarize the current evidence on the potential applications of oral budesonide in oncology, highlighting its promise as a targeted and well-tolerated treatment option for managing gastrointestinal immune-related toxicities that preserves the anti-cancer efficacy of immunotherapy.

Opinion statement: Endocrine therapy is the backbone of treatment for HR + /HER2- MBC. The introduction of novel endocrine-based therapies has changed the landscape of metastatic breast cancer care, with even more promising agents on the horizon. Given the consistent success in prolonging PFS and OS, CDK4/6 inhibitors should be used as first-line treatment. Once secondary resistance eventually develops after use of a CDK4/6 inhibitor, use of monotherapy with either AI or fulvestrant has shown poor outcome. For example, in the control group of the EMERALD trial, in which all the patients were required to have previously received a CDK4/6 inhibitor, median progression-free survival with endocrine therapy was only 1.9 months. Based on the emerging evidence, molecular profiling of tissue or liquid biopsy at progression of disease is crucial to select future therapy. For patients whose tumors harbor ESR1 mutations, oral SERDs are the preferred option. For those with PIK3CA or AKT1 mutation or PTEN inactivation, combination therapy with the AKT pathway inhibitor capivasertib is recommended. Alpelisib, the first AKT1 inhibitor approved in combination therapy with fulvestrant in PIK3CA mutated tumors only, is now less in favor given its challenging side effect profile. When mutations are not present, options include combination therapy with the mTOR inhibitor everolimus or changing endocrine therapy and continuing a CDK 4/6 inhibitor. In patients with short response to CDK4/6 inhibitors suggesting endocrine resistant disease, chemotherapy or antibody-drug conjugates should be considered. With better understanding of the mechanisms of resistance to CDK4/6 inhibitors, additional mutations could be identified and potentially targeted in order to provide individualized treatment options. Optimal sequencing of treatment options depends on several factors: (1) the presence of specific molecular aberrations; (2) previous treatment history, duration of response and patient's performance status; (3) balance between maximizing survival benefits with quality of life/toxicities; (4) disease burden. In the upcoming years, we anticipate FDA approvals for more of the SERD molecules both in monotherapy and in combination therapy which will continue to expand the options available for HR + /HER2- MBC patients.

Opinion statement: Prostate-specific membrane antigen targeted radionuclide therapies (PSMA-TRT) such as 177Lu-PSMA-617 hold great promise in improving clinical outcomes at various stages of prostate cancer. The FDA approval of 177Lu-PSMA-617 represents a significant advancement in the treatment of metastatic castration-resistant prostate cancer (mCRPC). The VISION trial demonstrated improved radiographic progression-free survival (rPFS) and overall survival (OS) with 177Lu-PSMA-617 in patients with mCRPC who had already receive androgen receptor pathway inhibitor (ARPI) and taxane chemotherapy. Exploration of 177Lu-PSMA-617 in earlier stages of prostate cancer, such as in the PSMAfore trial for patients who have not received chemotherapy, holds great promise for improving long-term outcomes and delaying exposure to chemotherapy. Combining 177Lu-PSMA-617 with other therapies, including chemotherapy, PARP inhibitors, and immunotherapy, is an area of active investigation. This review will also discuss alternative radionuclides (such as actininum-225 and terbium-161) and delivery vehicles (such as PSMA-I&T), which we find promising. Predictive biomarkers and dosimetry will be crucial for identifying patients most likely to benefit from PSMA-TRT. Continued research and refinement of these therapies will lead to PSMA-targeted treatments becoming an integral part of prostate cancer management.

Opinion statement: Esophageal cancer (EC), one highly malignant upper gastrointestinal cancer, is the eighth most commonly occurring cancer and the sixth leading cause of cancer-related deaths worldwide. Clinically, this malignancy is considered to be one of the most difficult-to-treat cancers, owing to its resistance to common therapies like chemotherapy and radiotherapy, and few targeted therapies are available. There is currently an unmet need for treatment of EC. Polyphenols are naturally occurring plant secondary metabolites in response to environmental threats and injury. Epidemiological evidence suggests that long-term consumption of a polyphenol-rich diet is inversely associated with the risk of cancer. Currently, natural polyphenols have received increased attention for their potential therapeutic effects on EC. In this review, we summarize and discuss recent progress in the therapeutic potential of natural polyphenols in EC, as well as their sources, oral bioavailability, and pharmacokinetics. We review natural polyphenols combined with approved chemotherapy and radiotherapy to overcome challenges faced by either monotherapy. We also discuss the current challenges and future directions to accelerate the clinical application of natural polyphenols in EC. We concluded that natural polyphenols represent promising candidates for the management of EC. Well-designed randomized controlled studies are warranted to verify the efficacy and safety of natural polyphenols for EC. Knowledge gained from this review will outline possible future research directions and should help to develop new therapeutics for this disease.

Opinion statement: Liquid biopsies represent a promising and minimally invasive approach to diagnosing and monitoring cancer. In recent years, studies across a multitude of solid organ malignancies have suggested the clinical utility of biomarkers such as circulating tumor DNA (ctDNA). Particular attention has been given to serial assessment of such biomarkers in an effort to detect minimal residual disease (MRD), in order to predict which patients may be at highest risk of relapse following curative-intent surgical or medical intervention. Such investigations are particularly relevant to sarcomas, which are highly heterogeneous malignancies and commonly develop treatment resistance. While preliminary research described herein is promising, there remain key barriers to widespread adoption of liquid biopsy in sarcoma, including the lack of standardized detection methods, high cost, and the need for large, prospective studies to validate their clinical utility. Given the high level of interest in liquid biopsy in the biomedical community, it is plausible such obstacles may be overcome in the near future. With such advancements, one can anticipate that liquid biopsies may become a key tool in the sarcoma oncologists armamentarium, and offer a path toward improved outcomes for patients with sarcoma.

Opinion statement: Gastrointestinal stromal tumors (GIST) are the most common gastrointestinal soft tissue sarcomas, with an incidence of about 15 cases per million person-years. Approximately 15% of GIST develop due to succinate dehydrogenase deficiency (SDH-Def), and such tumors do not respond well to the tyrosine kinase inhibitors (TKIs) used to treat other GIST. Due to its indolent nature SDH-Def GIST can often be surveilled if asymptomatic. In our current practice we typically treat advanced symptomatic SDH-Def GIST with the anti-angiogenic TKIs, sequentially treating with sunitinib, regorafenib and pazopanib. This practice is based on limited data. This systematic review provides an update on new data (12/21/2021 to 9/26/2024) for systemic treatment of SDH-Def GIST, both with agents generally used to treat other GIST subtypes and with agents approved in other malignancies. Olverembatinib and rogaratinib have shown promising activity in pre-clinical models and small SDH-Def GIST cohorts. Other agents whose benefits are explored here include the immune checkpoint inhibitors (ICI) ipilimumab and nivolumab and temozolomide, whether as monotherapy or in combination with INBRX-109 (a pro-apoptotic antibody) or olaparib. Additional research into TKI agents with anti-vascular endothelial growth factor receptor (VEGFR) and anti-fibroblast growth factor receptor (FGFR) activity in this clinical setting is needed. Patients with SDH-Def will benefit more broadly from ongoing explorations of treatments with alternative mechanisms of action, especially those that exploit cellular pathways involved in SDH-Def GIST tumorigenesis.

Opinion statement: Recent clinical trials have investigated immune checkpoint inhibitors (ICIs) alone, in combination with tyrosine kinase inhibitors (TKIs), or with chemotherapy in angiosarcoma, yielding mixed results across subtypes. Single-agent ICI therapy, such as cemiplimab (ORR 27.8%), has shown responses primarily in UV- and radiation-associated angiosarcomas, likely due to their higher tumor mutation burden (TMB), while dual ICI therapy (SWOG S1609, ORR 25%) suggests potential benefit but remains limited in cutaneous disease. ICI-TKI combinations, such as cabozantinib plus nivolumab (Alliance A091902, second-line, ORR 59%), demonstrated significant efficacy in both cutaneous and non-cutaneous angiosarcomas, suggesting anti-angiogenic therapy may enhance ICI responses in tumors historically resistant to checkpoint blockade. ICI-chemotherapy combinations have been less consistent. The Alliance A091902 first-line trial (paclitaxel ± nivolumab) found no overall PFS benefit, though scalp/face angiosarcoma patients appeared to fare better, raising the question of whether ICI alone might be equally effective in this subset. The South Korean paclitaxel + avelumab trial (ORR 50%) showed promising response rates, but the lack of detailed subgroup analysis limits interpretation. Other chemotherapy-ICI combinations, such as doxorubicin plus pembrolizumab, have shown isolated responses but require further study in larger cohorts. Moving forward, better biomarkers are critical for identifying which patients benefit most from ICIs, and while TKI-ICI combinations appear to hold the most promise, chemotherapy-ICI strategies need further refinement to optimize sequencing and patient selection in angiosarcoma treatment.