Therapeutic Advances in Medical Oncology最新文献

Background: Sunitinib, a multitarget tyrosine kinase inhibitor, showed encouraging antitumor activity and manageable toxicity in patients with advanced midgut neuroendocrine tumors (NETs) in earlier results from phase I and II trials.

Patients and methods: In this phase II trial, patients with a nonresectable grade 1 or 2 midgut progressive NET and Eastern Cooperative Oncology Group performance status 0-1 were randomly assigned 1:1 to receive 37.5 mg sunitinib or a placebo, combined with 120 mg lanreotide autogel every 28 days. The planned sample size was 104 patients. The primary outcome was investigator-assessed progression-free survival (PFS).

Results: The study was stopped early because of insufficient patient recruitment. Between January 2013 and December 2016, 44 patients were enrolled and received sunitinib (n = 22) or placebo (n = 22). The median age was 63.7 years (Q1-Q3 range, 56.6-68.1) and 26 patients (59.1%) were male. The main localization was ileum (N = 37, 84.1%) and the majority were grade 2 (n = 25, 56.8%). The median follow-up was 36.7 months (95% confidence interval (CI) 34.6-48.2). The median PFS was 9.84 months (95% CI 6.8-23.3) with sunitinib and 11.47 months (95% CI 5.4-15.3) with placebo (hazard ratio (HR) = 0.80, 95% CI 0.41-1.56, p = 0.51). There was no difference in overall survival between treatment arms (HR = 0.81, (95% CI 0.32-2.01), p = 0.64). The objective response rate was 9.1% with sunitinib and 0.0% with placebo, and 19 patients (86.4%) had stable disease. Thirty-nine patients (88.6%) completed the baseline QLQ-C30 questionnaire. Baseline health-related quality of life level was similar between treatment arms, except for physical and emotional functioning which were higher (p = 0.089) and lower (p = 0.023) in the sunitinib arm, respectively. Trends toward longer time until a definitive deterioration in favor of the sunitinib arm were observed for 10 out of 15 dimensions (HRs < 1), with a significant result for financial difficulties (HR = 0.31, (90% CI 0.10-0.94)). Twenty-seven patients (61.4%) had at least one adverse event grade ⩾3 (sunitinib: 72.7%, placebo: 50.0%), with only one patient grade 4 for hypertension and vomiting. Eleven deaths non-related to treatment occurred (sunitinib arm: n = 5, placebo arm: n = 6).

Conclusion: Our study does not provide enough evidence to conclude the role of sunitinib in advanced midgut NETs, primarily due to a lower-than-expected number of enrolled patients. While we cannot entirely rule out the efficacy of sunitinib, lanreotide alone may play a significant role.

Trial registration: EudraCT: 2012-001098-94.

Background: Immunotherapy combined with intra-arterial therapy (IAT) has shown great potential in the treatment of unresectable hepatocellular carcinoma (uHCC). However, there are currently no available biomarkers that can predict the prognosis of immune-based combined therapy.

Objectives: To establish a scoring method to predict prognosis in uHCC patients undergoing IAT plus immunotherapy.

Methods: Between March 2019 and August 2022, uHCC patients undergoing IAT in combination with programmed cell death (ligand) 1 (PD-1)/PD-L1-based immunotherapy were retrospectively analyzed.

Results: Among 1046 patients included, 780 patients were enrolled into hepatic arterial infusion chemotherapy immunotherapy cohorts (training set: n = 546, one center; external testing set: n = 234, three centers) and 266 patients were treated with trans-arterial chemoembolization (TACE) plus immunotherapy were enrolled into TACE immunotherapy cohort (validation set: n = 266). We developed the easy-to-apply alpha-fetoprotein (AFP), C-reactive protein (CRP), and platelet-to-lymphocyte ratio (PLR) in immunotherapy (AFCRPLITY) score and investigated the prognostic value of baseline variables on the disease control rate (DCR) and progression-free survival (PFS). HCC patients with low AFCRPLITY scores would have better PFS and DCRs than patients with high AFCRPLITY scores (AFCRPLITY 0: vs AFCRPLITY 1: vs AFCRPLITY 2: vs AFCRPLITY 3: p < 0.001 for PFS, p = 0.001 for DCRs) in the training set, which was confirmed in the external testing set and validation set. The highest level of CD8+ T cells was in the AFCRPLITY score = 0 group than the other two groups.

Conclusion: The AFCRPLITY score is associated with PFS and DCR in uHCC patients receiving IATs plus immunotherapy. This score may be helpful for counseling, but prospective validation is needed.

Design: A retrospective, multi-institutional study.

Trial registration: The study has been retrospectively registered at the Chinese Clinical Trial Registry (https://www.chictr.org.cn/, ChiCTR2300075828).

While the clear-cell renal cell carcinoma (ccRCC) treatment has undergone several paradigm shifts in recent years, the non-clear cell renal cell carcinoma (nccRCC) therapeutic approach has yet to be extensively investigated and improved. The WHO 2022 classification of renal neoplasms redefined the most common nccRCC subtypes (papillary and chromophobe RCC) and introduced the molecularly defined RCC class, which is a first step in the direction of better molecular profiling of nccRCC. We reviewed the literature data on known genomic alterations of clinical interest in nccRCC and discussed their potential role in guiding therapeutic choices in each nccRCC entity. Among the alterations discussed, we focused on the ones that could be treated with already available drugs, such as MET-driven papillary RCC, mechanistic target of rapamycin altered chromophobe RCC, anaplastic lymphoma kinase-rearranged RCC, and fumarate-hydratase deficient RCC. Furthermore, we focused on the currently ongoing clinical trials and further evidence for all the other entities, such as SMARCB1-deficient RCC, TFE3 and transcription factorEB (TFEB)-altered RCC, and Elongin C (ELOC)-mutated RCC. The vast heterogeneity of nccRCC does not allow a one-size-fits-all solution; therefore, molecular characterization is the path toward effective therapies and fully personalized medicine for these entities.

Background: Everolimus is beneficial for patients with hormone receptor-positive and human epidermal growth factor receptor 2-negative (HR+/HER2-) advanced breast cancer (ABC). However, some patients developed drug resistance and the well-established predictor for everolimus efficacy was limited.

Objectives: The study was designed to evaluate the efficacy of everolimus in different treatment lines and identify several clinicopathological markers to estimate everolimus efficacy in patients with HR+/HER2- ABC.

Design: This was a retrospective and multicenter study.

Methods: Between 2014 and 2022, more than 2000 patients with tumors who received everolimus were collected from multiple cancer centers in China (National Cancer Center, Chinese PLA General Hospital, Peking University Cancer Hospital & Institute). A training cohort and two validation cohorts were developed.

Results: The training cohort included 338 patients. The median progression-free survival (PFS) for everolimus was 5.6 months, with an objective response rate of 25.1% and a clinical benefit rate of 54.4%. PFS was significantly worse from first-line (1L) to second-line (2L) to third-line (3L), with PFS_1L for 13.5 months, PFS_2L for 6.1 months, and PFS_3L for 4.1 months (p = 2.9e-6, hazard ratio (HR) = 0.70, 95% confidence interval (CI) = 0.61-0.82). The clinicopathological characteristics, including post-1L everolimus treatment, Ki67 index of more than 40%, more than two metastatic sites at first recurrence, and receiving adjuvant chemotherapy, were independent risk factors for PFS. A predictive model for everolimus efficacy was established using these four factors. In the low-risk group, patients achieved a median PFS of 12.6 months, significantly longer compared to 2.7 months for those in the high-risk group (p = 2.4e-64, HR = 9.41, 95% CI = 7.05-12.56). The area under the curve was 0.96, 0.95, and 0.94 for 6-month, 1-year, and 3-year PFS, respectively. Internal validation cohort (PFS 18.4 vs 3.1 months, p = 3.6e-11, HR = 3.78, 95% CI = 2.49-5.74) and external validation cohort (PFS 13.5 vs 3.1 months, p = 2.9e-10, HR = 11.53, 95% CI = 4.68-28.37) confirmed its power for estimating clinical benefits of everolimus.

Conclusion: A predictive model was successfully established to predict survival outcomes for everolimus in patients with HR+/HER2- ABC, which may provide references for the management of everolimus in Chinese patients with HR+/HER2- ABC.

Background: Due to the rarity of sinonasal squamous cell carcinoma (SNSCC), the distribution patterns of lymph node metastasis (LNM), the relationship between LNM and prognosis, and the optimal treatment of LNM lack sufficient evidence-based support.

Objectives: To investigate the patterns of LNM in SNSCC and evaluate the impact of LNM on prognosis.

Design: This was a retrospective cohort study.

Methods: The medical records of 441 patients with SNSCC between 2009 and 2022 in one institution were retrospectively reviewed. We assessed the incidence, the distribution of LNM, and the relationship between LNM and long-term survival.

Results: Seventy-three out of 441 patients (16.6%) presented LNM initially. Among the 73 patients, 34 patients (46.6%) had LNM in the region of ipsilateral level II; 22 patients (30.1%) had positive retropharyngeal lymph nodes; 20 patients (27.4%) had LNM in the region of ipsilateral level Ib; and nine patients (12.3%) had evidence of parotid LNM. Poor differentiation (p = 0.001), nasal cavity (p = 0.018), skin involvement (p = 0.036), and nasopharynx involvement (p = 0.009) were the risk factors for LNM. In the univariate and multivariate analyses, the overall survival (p = 0.25), progression-free survival (p = 0.22), regional failure-free survival (p = 0.20), and distant metastasis-free survival (p = 0.14) rates were not significantly decreased by the LNM. After the propensity score matching, LNM was still not correlated with poor long-term survival.

Conclusions: The incidence of retropharyngeal and parotid LNM was higher than in previous studies. At initial diagnosis, the risk factors for LNM were identified, and LNM was not associated with poor survival outcomes.

Background: Repeat transurethral resection of bladder tumour (reTURB) is a conventional treatment for non-muscle-invasive bladder cancer (NMIBC) to enhance prognosis. However, the necessity of reTURB in NMIBC remains controversial owing to upstaging of treatments and new evidence.

Objectives: We performed an umbrella review to determine the need for reTURB in patients with NMIBC.

Design: We extracted data from meta-analyses that were screened out after a systematic search of PubMed, Embase, the Web of Science and the Cochrane Database of Systematic Reviews.

Methods: Risk of Bias in Systematic Reviews and the Grading of Recommendations, Assessment, Development and Evaluation tools were used to assess the quality of each included meta-analysis and outcomes.

Results: Our study included seven meta-analyses. Two studies assessed the efficiency of reTURB in patients who underwent en bloc resection of bladder tumours (ERBT). Patients who underwent ERBT reported low residual tumour and upstaging rates of 5.9% and 0.3%, respectively. Conversely, patients who underwent conventional transurethral resection for bladder cancer (cTURB) had high residual tumour rates. Patients who underwent cTURB and reTURB had significantly improved 1-year recurrence-free survival (RFS) compared to those who underwent initial cTURB alone. In terms of progression-free survival (PFS), a meta-analysis reported that patients who underwent cTURB and reTURB had significantly improved PFS compared with those who underwent initial cTURB alone. In the subgroup analyses of ERBT, reTURB did not affect the RFS and PFS of patients who received ERBT. Currently, only a limited number of randomised clinical trials have evaluated reTURB, and various factors have influenced its efficacy.

Conclusion: There was significant variation in survival outcomes among patients undergoing reTURB. The necessity and efficacy of reTURB depend on numerous factors, such as surgical approach, equipment and medication usage. Patients eligible for ERBT may constitute a group that does not require reTURB. Further clinical trials are required to validate these findings.

Registration: This umbrella review was registered with the International Prospective Register of Systematic Reviews (CRD42023439078).

Ewing sarcoma is a rare malignant neoplasm that primarily affects bone in children. Extraskeletal location is less common, while intradural extramedullary Ewing sarcoma (IEES) in adults is a casuistic phenomenon. Due to its rarity, a standardized treatment strategy for IEES has not been established. The clinical use of proton beam therapy (PBT) for craniospinal irradiation (CSI) in the treatment of IEES has not been reported in the literature. A 41-year-old previously healthy man presented with disabling gluteal and lower extremity pain, decreased sensation, and progressive paraparesis without sphincter dysfunction. Imaging showed intradural extramedullary spinal lesions. The patient underwent urgent surgery. Histology and immunohistochemistry suggested a poorly differentiated neuroendocrine tumor. Negative chromogranin staining and a high Ki67 index prompted further investigation. Next-generation sequencing later confirmed an EWSR1/FLI1 translocation, leading to the diagnosis of extraskeletal Ewing sarcoma. The patient received standardized chemotherapy with marked clinical improvement. PBT CSI was initiated but was interrupted due to COVID-19 and other complications. At 20 months follow-up, no recurrence was observed, and the patient reported an active life. Despite intra-spinal spread and multiple complications, intensive chemotherapy combined with PBT CSI led to a favorable outcome. CSI rather than focal radiotherapy should be considered for patients with IEES limited to the cerebrospinal axis. PBT may be used as an alternative to photon radiotherapy to better spare organs at risk.

Background: The NOVA study (NCT01847274) compared niraparib with placebo as a maintenance treatment for patients with recurrent ovarian cancer (OC) but was not powered to detect an overall survival (OS) improvement.

Objective: To compare OS in a real-world population of patients with BRCA wild-type (BRCAwt) recurrent OC who received second-line maintenance (2LM) niraparib monotherapy versus active surveillance (AS).

Design: A retrospective study using a US-based nationwide deidentified electronic health record-derived database.

Methods: Patients diagnosed with epithelial OC (January 1, 2011-May 31, 2021) who completed second-line (2L) therapy (January 1, 2017-March 2, 2022) and were BRCAwt were included. A NOVA study-like subpopulation included patients with an Eastern Cooperative Oncology Group performance status score of 0-1 and platinum-sensitive disease. Patients were assigned to 2LM niraparib or AS cohorts. Follow-up was measured from the index date (2L non-maintenance therapy end) until the first of study end (May 31, 2022), last clinical activity, or death. Median OS (mOS) and hazard ratios were estimated with an emulated trial methodology.

Results: The overall population comprised 199 patients in the 2LM niraparib monotherapy cohort and 707 patients in the AS cohort; the NOVA study-like subpopulation included 123 patients in the 2LM niraparib monotherapy cohort and 143 in the AS cohort. Demographic and clinical characteristics were similar in both populations. Overall, adjusted mOS was 24.1 months for the 2LM niraparib monotherapy cohort versus 18.4 months for the AS cohort (hazard ratio, 0.8; 95% confidence interval [CI]: 0.7-0.9). In the NOVA study-like subpopulation, adjusted mOS was 28.1 months for the 2LM niraparib monotherapy cohort versus 21.5 months for the AS cohort (hazard ratio, 0.6; 95% CI: 0.5-0.9).

Conclusion: These results provide important real-world OS data for patients with recurrent BRCAwt OC who received niraparib monotherapy compared with patients receiving AS.

Breast cancer (BC) is the leading cause of cancer-related mortality among women, and hormone receptor (HR)-positive subtype makes up the majority of all cases. The standard of care in HR⁺/HER2^- metastatic BC (MBC) is endocrine therapy (ET) plus a CDK4/6 inhibitor (CDK4/6i). ESR1 mutations could impair the clinical efficacy of the ETs. Similarly, PIK3CA mutations may serve as a negative prognostic marker. Furthermore, MBC is challenging to treat despite new drug approvals. Our patient received multiple lines of ET ± CDK4/6i and chemotherapy but persistently progressed after each or stopped the treatment due to adverse events. Here we showed for the first time that an all-oral combination of elacestrant plus alpelisib was feasible, tolerable, and clinically active in an ESR1 and PIK3CA co-mutated and heavily pretreated patient. We achieved a remarkable response in the metastatic lesions with minor toxicity issues. This case highlights the importance of utilizing up-to-date therapeutic agents and reactive decision-making during personalized cancer treatment.

Breast cancer remains a leading cause of brain metastases (BM), which carry a poor prognosis. The current approach to managing BMs in breast cancer patients involves a combination of local therapies (surgery, radiotherapy) and systemic treatments. Developing newer antibody-drug conjugates (ADCs) has sparked a revolution in metastatic breast cancer (MBC) care. ADCs such as ado-trastuzumab emtansine, trastuzumab deruxtecan, and sacituzumab govitecan have demonstrated significant improvement in patient outcomes and are standard of care in the treatment of MBC. Most of the ADC registration studies included patients with stable BMs but excluded individuals with active BM, making intracranial (IC) response assessment a challenge. Promising data has recently emerged, suggesting relevant IC activity for certain ADCs and ongoing studies in patients with active BM that will expand our knowledge. This review aims to summarize the effectiveness of approved ADCs as well as promising new ADCs in development for breast cancer with BM.