Cancer treatment reviews最新文献

Immunotherapy has revolutionized cancer therapy and now represents a standard of care for many tumor types, including triple-negative breast cancer. Despite the positive results that have led to the approval of immunotherapy in both early- and advanced-stage triple-negative breast cancer, pivotal clinical trials cannot address the myriad questions arising in everyday clinical practice, often falling short in delivering all the information that clinicians require. In this manuscript, we aim to address some of these practical questions, with the purpose of providing clinicians with a guide for optimizing the use of immune checkpoint inhibitors in the management of breast cancer patients and identifying opportunities for future research to clarify unresolved questions.

Therapeutic agents targeting Human Epidermal Growth Factor Receptor 2 (HER2) demonstrated to positively impact the prognosis of HER2-positive breast cancer. HER2-positive breast cancer can present either as hormone receptor-negative or positive, defining Triple-positive breast cancer (TPBC). TPBC demonstrate unique gene expression profiles, showing reduced HER2-driven gene expression, as recapitulated by a higher proportion of Luminal-type intrinsic subtypes. The different molecular landscape of TPBC dictates distinctive clinical features, including reduced chemotherapy sensitivity, different patterns of recurrence, and better overall prognosis. Cross-talk between HER2 and hormone receptor signaling seems to be critical to determine resistance to HER2-directed agents. Accordingly, superior outcomes have been achieved with the use of endocrine therapy, representing the first subtype-specific pharmacological intervention unique to this subgroup. Additional targeted agents capable to tackle resistance mechanisms to anti-HER2, hormone agents, or both might further improve the efficacy of treatments, such as PI3K/AKT/mTOR inhibitors, particularly in a biomarker-enriched setting, and CDK4/6-inhibitors, with preliminary data suggesting a role of PAM50 subtyping to predict higher benefits in luminal tumors. Finally, the distinct biology of triple-positive tumors may yield the rationale for considering combinations within antibody-drug conjugate regimens. Accordingly, in this review, we summarized the current evidence and rationale for considering TPBC as a different entity, in which distinct therapeutical approaches leveraging on the different biological profile of TPBC may result in superior anticancer regimens and improved patient-centric outcomes.

Background

Local resection (LR) methods for rectal cancer are generally considered in the palliative setting or for patients deemed a high anaesthetic risk. This systematic review and meta-analysis aimed to compare oncological outcomes of LR and radical resection (RR) for early rectal cancer in the context of staging and surveillance assessment.

Methods

A literature search of MEDLINE, Embase and Emcare databases was performed for studies that reported data on clinical outcomes for both LR and RR for early rectal cancer from January 1995 to April 2023. Meta-analysis was performed using random-effect models and between-study heterogeneity was assessed. The quality of assessment was assessed using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias 2.0 tool for randomised controlled trials.

Results

Twenty studies with 12,022 patients were included: 6,476 patients had LR and 5,546 patients underwent RR. RR led to an improvement in 5-year overall survival (OR 1.84; 95 % CI 1.54–2.20; p < 0.0001; I² 20 %) and local recurrence (OR 3.06; 95 % CI 2.02–4.64; p < 0.0001; I² 39 %) when compared to LR. However, when staging and surveillance methods were clearly adopted in LR cases, there was an improvement in R0 rates (96.7 % vs 85.6 %), 5-year disease-free survival (93.0 % vs 77.9 %) and overall survival (81.6 % vs 79.0 %) compared to when staging and surveillance was not reported/performed.

Conclusions

LR may be appropriate for selected patients without poor prognostic factors in early rectal cancer. This study also highlights that there is currently no single standardised staging or surveillance approach being adopted in the management of early rectal cancer. A more specified and standardised preoperative staging for patient selection as well as clinical and image-based surveillance protocols is needed.

Surgery is a standard treatment for early-stage gastrointestinal cancers, often preceded by neoadjuvant chemo(radio)therapy or followed by adjuvant therapy. While leading to cure in a proportion of patients, it has some drawbacks such as intra/post-operative complications, mutilation and life-long functional sequelae. Further to the unprecedented efficacy data from studies of immune checkpoint inhibitors for advanced mismatch repair deficient/microsatellite instable (dMMR/MSI-H) tumours, a strong interest has recently emerged for the investigation of such agents in the neoadjuvant setting. Although limited by the exploratory design and small sample size, trials of neoadjuvant immune checkpoint inhibitors for early-stage dMMR/MSI-H gastrointestinal cancers have consistently reported complete response rates ranging from 70 % to 100 %. As a result, the question has arisen as to whether surgery is still needed or organ-preserving strategies should be offered to this especially immuno-sensitive population. In this article, we discuss the available evidence for neoadjuvant immune checkpoint inhibitors in dMMR/MSI-H gastrointestinal cancers and analyse opportunities and challenges to the implementation of non-operative management approaches in this setting.

Chemotherapy associated with Immune Checkpoint Inhibitors is currently the standard of care in several tumor indications. This combination approach improves progression free survival (PFS), overall survival (OS) and complete pathological response (pCR) in several cancer types both in the early and metastatic approaches. However, the distinct spectrum of toxicities between cytotoxic side effects and immune related adverse events (irAEs) with similar clinical presentations and different management strategies remains a challenge in daily practice for healthcare professionals. This review summarizes the most common toxicities reported in the randomized clinical trials that led to the subsequent FDA approval of these combinations, across tumor indications. We cite in particular: non-small cell lung cancer, small cell lung cancer, triple negative breast cancer, squamous cell carcinoma of the head and neck, gastric carcinoma, esophageal carcinoma, cervical carcinoma and biliary tract carcinoma.

We found that the combination of chemotherapy and immunotherapy was associated with an increased incidence of all grade adverse events (RR 1.11 [1.09; 1.12]) without an excess in treatment related mortality when compared to chemotherapy alone. We report also an increase in the incidence of serious adverse events (grade ≥ 3) (RR 1.16 [1.10;1.24]); in particular: high grade diarrhea, dyspnea, fatigue, rash and elevated liver enzymes.

Together with the collaboration of our institutional network of organ specialists with expertise in irAEs, we propose practical recommendations for physicians to enhance clinical care and management of patients undergoing treatment with combined ICI immunotherapy and chemotherapy.

Traditional chemotherapy-based adjuvant therapies for locally advanced pancreatic ductal adenocarcinoma (PDAC) have been associated with poor clinical outcomes driven partly by its complex anatomy and molecular heterogeneity. Treatment for PDAC is challenged by presence of a dense tumour microenvironment involving an interplay of multiple tumoural and stromal components which promote metastatic oncogenic behaviour. PDAC also involves aberrations in multiple signalling pathways with paucity of treatment options against the most common mutations including KRAS, TP53, CDKN2A and SMAD4. However, recent discovery of new mechanisms implicated in pancreatic carcinogenesis have led to identification of promising mechanistic therapeutic targets such as NET1 and ULK1. Early evidence also suggests the utility of targeting multiple DNA repair processes, modulators of DNA replication and major DNA damage response regulators. We explore the clinical rationale behind a neoadjuvant therapeutic strategy and emerging predictors of survival benefit associated with this approach. We also discuss challenges and opportunities originating from recent clinical trials evaluating neoadjuvant treatments composed of various combinations of radiotherapy, chemotherapy and immunotherapeutic regimens that have aimed to address some of these biological challenges. Selective treatment of patients harbouring specific genomic aberrations with targeted agents and immunotherapy can translate into optimum survival outcomes in PDAC. We also share perspectives on emerging prospective clinical evidence regarding stromal modifying agents, such as Tumour Growth Factor-Beta and Connective Tissue Growth Factor inhibitors along with novel vaccination-based approaches in improving PDAC outcomes.

Cancer cells merely exist in isolation; rather, they exist in an intricate microenvironment composed of blood vessels, signalling molecules, immune cells, stroma, fibroblasts, and the ECM. The TME provides a setting that is favourable for the successful growth and survivance of tumors. Angiogenesis is a multifaceted process that is essential for the growth, invasion, and metastasis of tumors. TME can be visualized as a “concert hall,“ where various cellular and non-cellular factors perform in a “symphony” to orchestrate tumor angiogenesis and create “Havoc” instead of “Harmony”. In this review, we comprehensively summarized the involvement of TME in regulating tumor angiogenesis. Especially, we have focused on immune cells and their secreted factors, inflammatory cytokines and chemokines, and their role in altering the TME. We have also deciphered the crosstalk among various cell types that further aids the process of tumor angiogenesis. Additionally, we have highlighted the limitations of existing anti-angiogenic therapy and discussed various potential strategies that could be used to overcome these challenges and improve the efficacy of anti-angiogenic therapy.

Clinical trials of prostate-specific membrane antigen (PSMA) targeted radiopharmaceuticals have shown encouraging results. Some agents, like lutetium-177 [177Lu]Lu-PSMA-617 ([¹⁷⁷Lu]Lu-PSMA-617), are already approved for late line treatment of metastatic castration-resistant prostate cancer (mCRPC). Projections are for continued growth of this treatment modality; [¹⁷⁷Lu]Lu-PSMA-617 is being studied both in earlier stages of disease and in combination with other anti-cancer therapies. Further, the drug development pipeline is deep with variations of PSMA-targeting radionuclides, including higher energy alpha particles conjugated to PSMA-honing vectors. It is safe to assume that an increasing number of patients will be exposed to PSMA-targeted radiopharmaceuticals during the course of their cancer treatment. In this setting, it is important to better understand and mitigate the most commonly encountered toxicities. One particularly vexing side effect is xerostomia. In this review, we discuss the scope of the problem, inventories to better characterize and monitor this troublesome side effect, and approaches to preserve salivary function and effectively palliate symptoms. This article aims to serve as a useful reference for prescribers of PSMA-targeted radiopharmaceuticals, while also commenting on areas of missing data and opportunities for future research.

Background & Aims

 The average five-year survival of metastatic renal cell carcinoma (mRCC) is 71%. However, there is significant variability in patient prognosis. Immune checkpoint inhibitors (ICIs) have been introduced into the treatment landscape of mRCC. This meta-analysis aimed to estimate progression-free and overall survival probabilities and identify possible outcome predictors of mRCC patients treated with ICI combination as first-line treatment.

Methods

 Studies comparing the combination of ICI combinations versus standard of therapy for first-line treatment of advanced renal-cell carcinoma were searched in MEDLINE, CANCERLIT, the Cochrane Controlled Trials Register, and the Cochrane Library from inception through September 2023. Data on patient populations and outcomes were extracted from each study by three independent observers and combined using the DerSimonian and Laird methods.

Results

 Six studies met the inclusion criteria. Globally, 5121 patients were included in this meta-analysis: 2556 patients treated with immune checkpoint inhibitors and 2565 with sunitinib as control. The ICI combination was associated with improved PFS (hazard ratio (HR) 0.68; 95 % confidence interval (CI), 0.56–0.81, p < 0.0001). Furthermore, ICI combination was also associated with OS improvement (HR 0.85; 95 % CI, 0.78–0.92, p = 0.001). There is no statistical increase in adverse events.

Conclusions

 Our findings show that PFS and OS are statistically increased in mRCC with ICI combination treatment by 32% and 15%, respectively.