Summary
Patients with advanced solid malignancies were enrolled to an open-label, single-arm, dose-escalation study, in which CRLX101 was administered intravenously over 60 min among two dosing ...schedules, initially weekly at 6, 12, and 18 mg/m
2
and later bi-weekly at 12, 15, and 18 mg/m
2
. The maximum tolerated dose (MTD) was determined at 15 mg/m
2
bi-weekly, and an expansion phase 2a study was completed. Patient samples were obtained for pharmacokinetic (PK) and pharmacodynamic (PD) assessments. Response was evaluated per RECIST criteria v1.0 every 8 weeks. Sixty-two patients (31 male; median age 63 years, range 39–79) received treatment. Bi-weekly dosing was generally well tolerated with myelosuppression being the dose-limiting toxicity. Among all phase 1/2a patients receiving the MTD (
n
= 44), most common grade 3/4 adverse events were neutropenia and fatigue. Evidence of systemic plasma exposure to both the polymer-conjugated and unconjugated CPT was observed in all treated patients. Mean elimination unconjugated CPT T
max
values ranged from 17.7 to 24.5 h, and maximum plasma concentrations and areas under the curve were generally proportional to dose for both polymer-conjugated and unconjugated CPT. Best overall response was stable disease in 28 patients (64 %) treated at the MTD and 16 (73 %) of a subset of NSCLC patients. Median progression-free survival (PFS) for patients treated at the MTD was 3.7 months and for the subset of NSCLC patients was 4.4 months. These combined phase 1/2a data demonstrate encouraging safety, pharmacokinetic, and efficacy results. Multinational phase 2 clinical development of CRLX101 across multiple tumor types is ongoing.
A nomogram was recently published by Sun et al. to predict overall survival (OS) and the additional benefit of concurrent chemoradiation (CCRT) vs. radiotherapy (RT) alone, in stage II NPC treated ...with conventional RT. We aimed to assess the predictors of OS and to externally validate the nomogram in the IMRT era. We analyzed stage II NPC patients treated with definitive RT alone or CCRT between 2001 and 2011 under the territory-wide Hong Kong NPC Study Group 1301 study. Clinical parameters were studied using the Cox proportional hazards model to estimate OS. The nomogram by Sun et al. was applied with 1000 times bootstrap resampling to calculate the concordance index, and we compared the nomogram predicted and observed 5-year OS. There were 482 patients included. The 5-year OS was 89.0%. In the multivariable analysis, an age > 45 years was the only significant predictor of OS (HR, 1.98; 95%CI, 1.15–3.44). Other clinical parameters were insignificant, including the use of CCRT (HR, 0.99; 95%CI, 0.62–1.58). The nomogram yielded a concordance index of 0.55 (95% CI, 0.49–0.62) which lacked clinically meaningful discriminative power. The nomogram proposed by Sun et al. should be interpreted with caution when applied to stage II NPC patients in the IMRT era. The benefit of CCRT remained controversial.
Background
The recent advancement in massively parallel sequencing technologies has empowered liquid biopsies, in particular circulating tumor DNA (ctDNA) analysis, to be the new paradigm in ...personalized cancer management. Plasma ctDNA detection overcomes the current limitations in tumor tissue procurement and serves as a convenient and non-invasive method to capture tumor heterogeneity and genetic evolution along patients' cancer journey.
Summary of findings
In breast cancer, the current clinical application of ctDNA includes real-time monitoring of tumor response, detection of drug-resistant clones, assessing dynamic variations in tumor mutational landscape, identifying actionable mutations, detecting minimal residual disease and screening of early tumor.
Purpose
This review aims to summarize the current clinical evidence of ctDNA application in the management of breast cancer.
The authors sought to 1) review the literature on the remote care model that uses remote patient monitoring software (RPMS) as key mechanisms in oncology care for symptom tracking and health ...information provision and (2) compare the remote care model to standard care in terms of health-related quality of life, symptom burden, health management self-efficacy, anxiety, and depression.
The search was conducted on March 23, 2022, in the Cochrane Library, MEDLINE/PubMed, PsycINFO, and CINAHL databases.
The primary strategies for applying digital technology in remote care models are patient-reported outcomes (PRO) tracking and health information delivery. Common PRO measurements applied in the RPMS include quality of life, symptom burden, self-efficacy, anxiety, and depression. Nine randomized controlled trials testing seven RPMS interventions were examined. Compared to standard care, remote patient monitoring via RPMS was related to greater quality of life and lower physical symptom burden during cancer therapy. The RPMS incorporated into routine clinical care with nurses providing remote monitoring performed better on PRO than that not integrated.
The RPMS-based remote care model improves patient outcomes during cancer treatment, and it is not inferior to standard care until the RPMS function is more integrated with existing clinical care.
Nurses are well-positioned to engage patients in self-care skills via RPMS and can play a vital role in integrating such a model of remote patient care into routine care practices.
Nasopharyngeal cancer (NPC) is one of the most difficult cancers in the head and neck region due to the complex geometry of the tumour and the surrounding critical organs. High-dose radical ...radiotherapy with or without concurrent platinum-based chemotherapy is the primary treatment modality. Around 10%-15% of NPC patients have their diagnosis at age after 70. The management of NPC in elderly patients is particularly challenging as they encompass a broad range of patient phenotypes and are often prone to treatment-related toxicities. Chronologic age alone is insufficient to decide on the management plan. Comprehensive geriatric assessment with evaluation on patients' functional status, mental condition, estimated life expectancy, comorbidities, risks and benefits of the treatment, patients' preference, and family support is essential. In addition, little data from randomized controlled trials are available to guide treatment decisions in elderly patients with NPC. In deciding which treatment strategy would be suitable for an individual elderly patient, we reviewed the literature and reviewed the analysis of primary studies, reviews, and guidelines on management of NPC. This review also summarises the current evidence for NPC management in elderly adults from early to late stage of disease.
Purpose
This study aimed to discover intra-tumor heterogeneity signature and validate its predictive value for adjuvant chemotherapy (ACT) following concurrent chemoradiotherapy (CCRT) in ...locoregionally advanced nasopharyngeal carcinoma (LA-NPC).
Materials and methods
397 LA-NPC patients were retrospectively enrolled. Pre-treatment contrast-enhanced T1-weighted (CET1-w) MR images, clinical variables, and follow-up were retrospectively collected. We identified single predictive radiomic feature from primary gross tumor volume (GTVnp) and defined predicted subvolume by calculating voxel-wised feature mapping and within GTVnp. We independently validate predictive value of identified feature and associated predicted subvolume.
Results
Only one radiomic feature, gldm_DependenceVariance in 3 mm-sigma LoG-filtered image, was discovered as a signature. In the high-risk group determined by the signature, patients received CCRT + ACT achieved 3-year disease free survival (DFS) rate of 90% versus 57% (HR, 0.20; 95%CI, 0.05–0.94;
P
= 0.007) for CCRT alone. The multivariate analysis showed patients receiving CCRT + ACT had a HR of 0.21 (95%CI: 0.06–0.68,
P
= 0.009) for DFS compared to those receiving CCRT alone. The predictive value can also be generalized to the subvolume with multivariate HR of 0.27 (
P
= 0.017) for DFS.
Conclusion
The signature with its heterogeneity mapping could be a reliable and explainable ACT decision-making tool in clinical practice.
•GARD is associated with locoregional control in NPC and may serve as a potential framework to personalize radiotherapy dose.•Radiosensitive tumors for which GARD-optimized doses were estimated at ...less than the current standard (<66 Gy) (64.1 %).•Moderately radiosensitive tumors for which GARD-optmized doses were similar to current standard (66–74 Gy) (21.7 %).•Radioresistant tumors that GARD proposes may require dose escalation above the current standard (>74 Gy) (14.1 %).
Locally advanced nasopharyngeal cancer (NPC) patients undergoing radiotherapy are at risk of treatment failure, particularly locoregional recurrence. To optimize the individual radiation dose, we hypothesize that the genomic adjusted radiation dose (GARD) can be used to correlate with locoregional control.
A total of 92 patients with American Joint Committee on Cancer / International Union Against Cancer stage III to stage IVB recruited in a randomized phase III trial were assessed (NPC-0501) (NCT00379262). Patients were treated with concurrent chemo-radiotherapy plus (neo) adjuvant chemotherapy. The primary endpoint is locoregional failure free rate (LRFFR).
Despite the homogenous physical radiation dose prescribed (Median: 70 Gy, range 66–76 Gy), there was a wide range of GARD values (median: 50.7, range 31.1–67.8) in this cohort. In multivariable analysis, a GARD threshold (GARDT) of 45 was independently associated with LRFFR (p = 0.008). By evaluating the physical dose required to achieve the GARDT (RxRSI), three distinct clinical subgroups were identified: (1) radiosensitive tumors that RxRSI at dose < 66 Gy (N = 59, 64.1 %) (b) moderately radiosensitive tumors that RxRSI dose within the current standard of care range (66–74 Gy) (N = 20, 21.7 %), (c) radioresistant tumors that need a significant dose escalation above the current standard of care (>74 Gy) (N = 13, 14.1 %).
GARD is independently associated with locoregional control in radiotherapy-treated NPC patients from a Phase 3 clinical trial. GARD may be a potential framework to personalize radiotherapy dose for NPC patients.
The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This study aimed to ...evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients.
In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety.
Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR.
Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning.
The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.
Background: The strategy of dual blockade of TGF-β and PD-L1 pathways has not been previously tested in platinum-refractory recurrent or metastatic nasopharyngeal cancer (R/M NPC) patients. This ...study aimed to evaluate the safety and efficacy of bintrafusp alfa in refractory R/M NPC patients. Methods: In this single-arm, single-centre phase II clinical trial, 38 histologically confirmed R/M NPC patients were enrolled and administered with bintrafusp alfa every 2 weeks. Primary endpoint was objective response rate (ORR) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1). Secondary endpoints included progression-free survival (PFS), overall survival (OS), duration of response (DOR), and safety. Findings: Thirty-eight patients were accrued (33 men; median age, 54 years). ORR was 23.7% (complete response, n = 2; partial response, n = 7). The median DOR was 19.2 months, median PFS was 2.3 months, median OS was 17.0 months, and 1-year OS rate was 63.2%. Unfortunately, 25 patients (65.7%) progressed within 8 weeks of treatment, 15 patients (39.5%) and 8 patients (21.1%) developed hyper-progressive disease (HPD) per RECIST v1.1 and tumor growth rate (TGR) ratio respectively. Sixteen patients (42.4%) experienced ≥ grade 3 treatment-related adverse events (TRAEs), most commonly anemia (n = 9, 23.7%) and secondary malignancies (n = 4, 10.5%). TRAEs led to permanent treatment discontinuation in 7 patients. Patients with strong suppression of plasma TGFβ1 level at week 8 were unexpectedly associated with worse ORR (9.1% vs 44.4%, P = 0.046) and development of HPD. There was no correlation between PD-L1 expression and ORR. Interpretation: Bintrafusp alfa demonstrated modest activity in R/M NPC but high rates of HPD and treatment discontinuation secondary to TRAEs are concerning. Funding: The project was supported by Alice Ho Miu Ling Nethersole Charity Foundation Professorship Endowed Fund and Merck KGaA.
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