Cancer最新文献

Background: The purpose of this study was to assess the eligibility criteria in randomized controlled trials (RCTs) in metastatic non-small cell lung cancer (NSCLC).

Methods: Eligible trials were phase 3 RCTs of systemic treatments for metastatic NSCLC, registered with the World Health Organization International Clinical Trials Registry Platform and started between 2009 and 2023. The odds of selected eligibility criteria were determined with multivariable logistic regression. Trends in the use of the eligibility criteria over time were assessed with the Fisher's exact test.

Results: A total of 274 of 386 trials (71%) excluded patients with an Eastern Cooperative Oncology Group (ECOG) score of >1; the odds of excluding these patients were higher in RCTs of chemotherapy (adjusted odds ratio [aOR], 3.46; 95% CI [confidence interval], 1.91-6.50; p < .001) and immunotherapy (aOR, 3.31; 95% CI, 1.58-7.21; p = .001) and in recent trials (aOR, 1.83; 95% CI, 1.09-3.10; p = .02). A total of 95 of 386 trials (24.6%) had an upper age limit of 85 years or younger; this was more likely in trials performed in Asia (aOR, 8.83; 95% CI, 3.27-28.24; p < .001). The proportion of trials with eligibility criteria concerning comorbidities did not significantly decrease over time (p > .05). None of the trials had any eligibility criteria concerning frailty.

Conclusions: The eligibility criteria in phase 3 RCTs in metastatic NSCLC continue to be strict. In some trials, judicious modifications of these criteria should be considered to improve the enrollment of clinically relevant populations of patients, especially older adults, individuals with an ECOG score of 2, and those with selected comorbidities.

Background: Social vulnerability, dietary fiber, and the gut microbiome have been individually implicated in clinical outcomes for melanoma and sarcoma patients. This study hypothesized that increasing social vulnerability is associated with insufficient dietary fiber intake and negatively associated with microbiome composition and clinical outcomes.

Methods: Clinicopathologic data, baseline fiber intake, and gut microbiome profiles were assessed in 153 patients with melanoma or sarcoma treated with immune checkpoint blockade (ICB) and prospectively followed. Patients' social vulnerability index (SVI) and fiber intake were evaluated for associations with microbiome composition, treatment response, and overall survival (OS).

Results: SVI percentile was 0.4 (interquartile ratio [IQR], 0.2-0.7), and median dietary fiber intake was 17 (IQR, 15-20) g/day. SVI was inversely correlated with dietary fiber intake (r, -0.18, p = .0398). Gut microbiome analyses revealed community and compositional differences by SVI, including inverse associations with α-diversity and the relative abundance of favorable bacteria such as Bifidobacterium longum (p < .001), contrasting the positive associations observed between fiber and these microbial markers. Increased dietary fiber intake was associated with measurable response to ICB. A difference in OS was not observed in more socially vulnerable patients (SVI, not reached vs. 81.7 months), however, a survival advantage was evident with higher dietary fiber intake (not reached, 58.9 months).

Conclusions: Increased social vulnerability was associated with a less favorable gut microbiome composition but not worse OS among melanoma and sarcoma patients treated with ICB. Consistent with prior findings, high dietary fiber intake emerged as a potentially modifiable pathway to improve outcomes in patients initiating ICB, particularly those with increased SVI.

Background: Mutations in genes encoding proteins involved the DNA damage response (DDR) occur in up to 20% of patients with cancer. It is unknown whether poly(adenosine diphosphate ribose) polymerase (PARP) inhibitors, alone or in combination with ATR or AKT inhibitors, have histology-agnostic clinical efficacy in tumors with DDR mutations or PI3K/AKT pathway mutations, respectively.

Methods: The Olaparib Combinations (OLAPCO) trial enrolled patients in treatment arms based on next-generation sequencing results. In cohorts 1 and 2, patients with tumors harboring DDR mutations received either the PARP inhibitor olaparib or olaparib and the ATR inhibitor ceralasertib. In cohort 3, patients with tumors with PI3K-AKT pathway alterations or ARID1A mutations received olaparib and capivasertib. The primary end point was overall response rate (ORR) at 16 weeks assessed by the Response Evaluation Criteria in Solid Tumors, version 1.1.

Results: Sixty-six patients were treated, including 26 on olaparib monotherapy, 24 on olaparib and ceralasertib, and 16 on olaparib and capivasertib. Among all patients treated, the ORR was 6.1% and the clinical benefit rate was 31.2% with a median duration of benefit (DoB) of 11 months. Among seven patients with platinum- and PARP inhibitor-resistant high-grade ovarian serous cancer in the olaparib and ceralasertib arm, one had a partial response and four had stable disease with a median DoB of 10 months. No unexpected toxicities were observed.

Conclusion: The study failed to meet its primary end point of ORR. DDR and homologous recombination repair defects are not consistently actionable with olaparib as monotherapy or in combination with other targeted therapies in a histology-agnostic manner.

Background: The current standard treatment for limited-stage small cell lung cancer (LS-SCLC) is concurrent chemoradiotherapy (cCRT) plus consolidation immunotherapy, with or without prophylactic cranial irradiation (PCI). However, it remains unknown whether administering immunotherapy concurrently with chemoradiotherapy confers additional benefit. This clinical trial is designed to investigate the efficacy and safety using durvalumab with chemoradiotherapy for LS-SCLC.

Methods: In this single-arm phase 2 study, patients with LS-SCLC received three (1-4) cycles of etoposide, cisplatin, or carboplatin, and durvalumab every 3 weeks, following by thoracic radiotherapy of 60.0 Gy to the gross tumor volume and 54.0 Gy to the planning target volume in 30 once-daily fractions and chemoimmunotherapy. After cCRT plus durvalumab, patients received durvalumab consolidation therapy every 3 weeks for a minimum of 1 year. PCI was recommended to patients with partial or complete response when chemoradiotherapy completed. Efficacy and adverse events were assessed.

Results: Overall, 51 patients were enrolled from March 1, 2021, to April 30, 2024, with a median follow-up of 32.0 months. The 1-, 2-, and 3-year progression-free survival (PFS) rates were 56.9%, 35.9%, and 28.2%, respectively, and the median PFS was 17.0 months. The 1-, 2-, and 3-year overall survival (OS) rates were 88.1%, 68.6%, and 49.6%, respectively, and the median OS was 32.0 months. There were 17 (33.4%) patients with grade 3 or 4 adverse events, 7 of which were immune‑related.

Conclusions: These results suggest that the addition of durvalumab to chemoradiotherapy was well tolerated and showed encouraging efficacy, supporting further investigation in patients with LS-SCLC eligible for radical chemoradiotherapy.

Background: Adults with advanced cancer often experience low engagement with advance care planning (ACP) and high levels of depression, anxiety, and fear of death/dying. Access to specialist palliative care is limited. This study tests Valued Living, a novel online acceptance-based group intervention designed to increase ACP and improve psychological/spiritual well-being among adults with advanced cancer screening positive for depression or anxiety. Valued Living was delivered online by social workers in community oncology settings.

Methods: Adults with advanced solid tumor cancer (N = 240) and significant depression or anxiety symptoms were randomized 1:1 within cohorts to Valued Living or usual care (UC). Valued Living provided five weekly group sessions by videoconference plus self-paced online modules. Primary outcome was the total number of ACP behavioral steps completed of 12 potential steps (e.g., selecting health care proxy, advanced directives) by 3.5-month follow-up. Secondary outcomes included fear of death, rigid cognitive avoidance of death, depression, anxiety, and spiritual well-being.

Results: Valued Living participants completed 1.27 more ACP steps (95% CI, 0.36-2.18; d = 0.36; p = .006) than UC. Largest condition differences were identifying (97.4% vs. 84.2%) and documenting a health care proxy (83.3% vs. 64.9%). Valued Living participants improved more in cognitive avoidance of death (d = 0.36; p = .005), and spiritual well-being (d = 0.42; p < .001) but not fear of death or anxiety.

Conclusion: The online Valued Living intervention, implemented by social workers in community oncology clinics, increased ACP and well-being among depressed and anxious adults with advanced cancer. Findings support this supportive care approach for the growing population living with advanced cancer.

Trial registration: The trial registration is ClinicalTrials.gov NCT04773639.

Background: NRG/RTOG 1010 evaluated trastuzumab added to trimodality therapy for HER2+ localized esophageal adenocarcinoma (EAC) management. Secondary PRO objectives assessed improvement in the FACT-Esophageal Cancer Subscale (ECS), version 4, with trastuzumab, and if improved ECS correlated with pathologic complete response (pCR).

Methods: Patients were randomized to weekly paclitaxel/carboplatin/radiation (chemoradiation, CRT) followed by surgery ± trastuzumab (CRT + Tras). Disease-free survival (DFS) was the primary end point. The projected PRO sample size of 158 patients, based on an 80% participation rate of the DFS primary endpoint sample size of 197 HER2+ patients, would provide ≥ 89% power to detect ≥25% increase in the proportion of CRT + Tras patients with ECS improvement from baseline to 6-8 weeks post-CRT; one-sided α = 0.05, using a χ² test. Improvement in ECS and its swallowing index (SI) and eating index (EI) was defined as 5-, 2-, and 2-point increases, respectively, from baseline to 6-8 weeks post-CRT. Univariate logistic regression was assessed if pCR was associated with improved ECS.

Results: From 2010 to 2015, 203 HER2+ patients were randomized and 194 were eligible. Of 171 PRO consenting patients, the ECS was completed by 162 (95%) at baseline, 108 (64%) 6-8 weeks, 82 (49%) 1 year, and 55 (33%) at 2 years. The proportion of patients with an improvement in 6-8 weeks ECS was higher on the CRT + Tras arm (46% vs. 38%), although not significantly different (p = .39). There was no correlation between pCR and ECS scores at 1 year, with 39% and 37% of pCR and non-pCR patients, respectively, having improved 1-year ECS scores.

Conclusions: The addition of trastuzumab to CRT for localized HER2+ EAC did not improve PROs.

Background: Ataxia telangiectasia Rad3-related (ATR) protein kinase regulates DNA damage response and is essential for tumor cell survival. Preclinically, ATR inhibition can sensitize tumor cells to radiation and chemotherapy. The authors conducted a phase 1 trial of berzosertib, a selective ATR inhibitor, in combination with definitive radiation and cisplatin in locally advanced head and neck squamous cell cancers (LA-HNSCC).

Methods: LA-HNSCC patients received daily radiation (2 Gy per fraction to 70 Gy) and weekly intravenous (iv) cisplatin 40 mg/m². Berzosertib was administered (iv) once weekly, starting with a pharmacokinetic lead-in dose. Three berzosertib dose levels (DL) were tested: 120 mg/m² (DL1), 160 mg/m² (DL2), and 200 mg/m² (DL3).

Results: Forty-one of 43 enrolled patients were evaluable for safety and preliminary efficacy assessments. Four patients experienced dose-limiting toxicities (DLTs) in dose-escalation: grade 4 thrombocytopenia (1), grade 4 respiratory failure (1), grade 3 renal injury and hypoxia (1), and inability to receive 90% of the planned radiation dose (1). DL3 was the recommended phase 2 dose, and 15 patients were enrolled at this DL as an expansion cohort. Objective response rates (ORR) in patient cohorts treated with any amount of berzosertib; treated with at least 50% of planned treatment; and in the expansion cohort were 78.8% (26 of 33), 78.8% (26 of 33), and 63.6% (7 of 11), respectively, after excluding eight inevaluable patients without post-treatment imaging assessment.

Conclusions: Berzosertib (200 mg/m² iv weekly) was safe when combined with chemoradiation but did not improve complete response rate in LA-HNSCC.