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•PSMA PET/CT indicated a previously unnoticed paired nasopharyngeal macroscopic salivary gland.•Presence of paired mucous glands was confirmed in 100 consecutive patients and cadaver ...histology.•In 723 patients, the radiotherapy dose to this area was associated with xerostomia and dysphagia.•We propose to name these newly identified macroscopic glands the “tubarial glands”.•Sparing these glands in radiotherapy provides an opportunity to improve quality of life.
The presence of previously unnoticed bilateral macroscopic salivary gland locations in the human nasopharynx was suspected after visualization by positron emission tomography/computed tomography with prostate-specific membrane antigen ligands (PSMA PET/CT). We aimed to elucidate the characteristics of this unknown entity and its potential clinical implications for radiotherapy.
The presence and configuration of the PSMA-positive area was evaluated in a retrospective cohort of consecutively scanned patients with prostate or urethral gland cancer (n = 100). Morphological and histological characteristics were assessed in a human cadaver study (n = 2). The effect of radiotherapy (RT) on salivation and swallowing was retrospectively investigated using prospectively collected clinical data from a cohort of head-neck cancer patients (n = 723). With multivariable logistic regression analysis, the association between radiotherapy (RT) dose and xerostomia or dysphagia was evaluated.
All 100 patients demonstrated a demarcated bilateral PSMA-positive area (average length 4 cm). Histology and 3D reconstruction confirmed the presence of PSMA-expressing, predominantly mucous glands with multiple draining ducts, predominantly near the torus tubarius. In the head-neck cancer patients, the mean RT dose to the gland area was significantly associated with physician-rated post-treatment xerostomia and dysphagia ≥ grade 2 at 12 months (0.019/gy, 95%CI 0.005–0.033, p = .007; 0.016/gy, 95%CI 0.001–0.031, p = .036). Follow-up at 24 months had similar results.
The human body contains a pair of previously overlooked and clinically relevant macroscopic salivary gland locations, for which we propose the name tubarial glands. Sparing these glands in patients receiving RT may provide an opportunity to improve their quality of life.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In locally advanced lung cancer, established baseline clinical variables show limited prognostic accuracy and 18F-fluorodeoxyglucose positron emission tomography (FDG PET) radiomics features may ...increase accuracy for optimal treatment selection. Their robustness and added value relative to current clinical factors are unknown. Hence, we identify robust and independent PET radiomics features that may have complementary value in predicting survival endpoints. A 4D PET dataset (n = 70) was used for assessing the repeatability (Bland-Altman analysis) and independence of PET radiomics features (Spearman rank: |ρ|<0.5). Two 3D PET datasets combined (n = 252) were used for training and validation of an elastic net regularized generalized logistic regression model (GLM) based on a selection of clinical and robust independent PET radiomics features (GLMall). The fitted model performance was externally validated (n = 40). The performance of GLMall (measured with area under the receiver operating characteristic curve, AUC) was highest in predicting 2-year overall survival (0.66±0.07). No significant improvement was observed for GLMall compared to a model containing only PET radiomics features or only clinical variables for any clinical endpoint. External validation of GLMall led to AUC values no higher than 0.55 for any clinical endpoint. In this study, robust independent FDG PET radiomics features did not have complementary value in predicting survival endpoints in lung cancer patients. Improving risk stratification and clinical decision making based on clinical variables and PET radiomics features has still been proven difficult in locally advanced lung cancer patients.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
•SPCT/CT-guided elective nodal irradiation spares the contralateral neck.•It is associated with a very low risk of contralateral nodal recurrence.•It leads to less dysphagia and xerostomia than ...standard bilateral treatment.•This, in turn, leads to a better quality of life.
Bilateral elective nodal irradiation (ENI) remains the standard treatment for head and neck squamous cell carcinoma (HNSCC). Unilateral ENI could reduce treatment toxicity and improve health-related quality-of-life (HRQOL). This prospective proof-of-principle trial (NCT02572661) investigated the feasibility, safety and clinical benefits of SPECT/CT-guided ENI of the node-negative contralateral neck.
Patients with lateralized T1-3N0-2bM0 HNSCC of the oropharynx, oral cavity, larynx and hypopharynx underwent SPECT/CT after peritumoral 99mTc-nanocolloid injection. Patients without contralateral lymph drainage received ipsilateral ENI only. If lymph drainage to only one contralateral hot spot was visible, ENI to the contralateral neck would be limited to only the level containing the hot spot. The primary endpoint was the incidence of contralateral regional failure (CRF) at 2 years. Toxicity and HRQOL were compared with a 1:1 matched historical cohort that received standard bilateral ENI (B-ENI) with identical planning and treatment techniques.
Fifty patients were treated with SPECT/CT-guided ENI. After a median follow-up of 33 months (range 18–45), CRF was observed in one patient (2%; 95% confidence interval: 0–6%). Compared to the matched B-ENI group, patients treated with SPECT/CT-guided ENI had significantly lower incidences of grade ≥2 dysphagia (54% vs. 82%; p < 0.001), tube feeding (10% vs. 50%; p < 0.001) and late grade ≥2 xerostomia (9% vs. 54%; p < 0.001). Significant and clinically relevant HRQOL benefits of SPECT/CT-guided ENI were observed on the EORTC QLQ-C30 summary score, and QLQ-HN35 swallowing and dry mouth subscales.
SPECT/CT-guided ENI is associated with a low risk of contralateral regional failure. Compared to B-ENI, SPECT/CT-guided ENI significantly reduces dysphagia, feeding tube placement, and late xerostomia and improves HRQOL.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Surgery for locoregionally advanced head and neck squamous cell carcinoma (HNSCC) results in 30‒50% five-year overall survival. In IMCISION (NCT03003637), a non-randomized phase Ib/IIa trial, 32 ...HNSCC patients are treated with 2 doses (in weeks 1 and 3) of immune checkpoint blockade (ICB) using nivolumab (NIVO MONO, n = 6, phase Ib arm A) or nivolumab plus a single dose of ipilimumab (COMBO, n = 26, 6 in phase Ib arm B, and 20 in phase IIa) prior to surgery. Primary endpoints are feasibility to resect no later than week 6 (phase Ib) and primary tumor pathological response (phase IIa). Surgery is not delayed or suspended for any patient in phase Ib, meeting the primary endpoint. Grade 3‒4 immune-related adverse events are seen in 2 of 6 (33%) NIVO MONO and 10 of 26 (38%) total COMBO patients. Pathological response, defined as the %-change in primary tumor viable tumor cell percentage from baseline biopsy to on-treatment resection, is evaluable in 17/20 phase IIa patients and 29/32 total trial patients (6/6 NIVO MONO, 23/26 COMBO). We observe a major pathological response (MPR, 90‒100% response) in 35% of patients after COMBO ICB, both in phase IIa (6/17) and in the whole trial (8/23), meeting the phase IIa primary endpoint threshold of 10%. NIVO MONO's MPR rate is 17% (1/6). None of the MPR patients develop recurrent HSNCC during 24.0 months median postsurgical follow-up. FDG-PET-based total lesion glycolysis identifies MPR patients prior to surgery. A baseline AID/APOBEC-associated mutational profile and an on-treatment decrease in hypoxia RNA signature are observed in MPR patients. Our data indicate that neoadjuvant COMBO ICB is feasible and encouragingly efficacious in HNSCC.
Since the introduction of radiolabeled prostate-specific membrane antigen (PSMA) PET/CT, the ability to visualize recurrent prostate cancer has improved substantially. However, diagnostic accuracy is ...largely lacking for radiolabeled PSMA PET/CT in patients with biochemical persistence (BCP; that is, persistently measurable prostate-specific antigen PSA values after robot-assisted laparoscopic radical prostatectomy RARP). Therefore, the aim of this study was to determine the role of PSMA (i.e.,
F-DCFPyL or
Ga-PSMA-11) PET/CT imaging in patients who experience BCP after RARP and to evaluate the sites of persistent disease on PSMA PET/CT.
In total, 150 consecutive patients with BCP after RARP who underwent radiolabeled PSMA PET/CT imaging were retrospectively evaluated. BCP was defined as any detectable first serum PSA value after RARP (≥0.1 ng/mL) at least 6 wk after surgery, in the absence of an undetectable PSA value after RARP. A multivariable logistic regression analysis was performed to identify predictors for the detection of metastases outside the prostatic fossa (≥miN1) on PSMA PET/CT.
PSMA PET/CT was performed at a median PSA value of 0.60 ng/mL (interquartile range, 0.3-2.4) after a median of 6 mo (interquartile range, 4-10) after RARP. In total, 101 of 150 patients (67%) had lesions with PSMA expression on PET/CT, and 89 of 150 (59%) had lesions with increased PSMA expression sites outside the prostatic fossa. Moreover, 39 of 150 patients (26%) had PSMA-positive lesions outside the pelvis. On multivariable analysis, higher PSA values after RARP (
= 0.004) and positive pathologic lymph node status (
= 0.006) were independent predictors for ≥miN1.
In the presence of BCP, a high proportion of patients already had disease metastatic to the pelvic lymph nodes or showed evidence of distant metastases, as indicated by PSMA PET/CT. Higher PSA levels after RARP and positive pathologic lymph node status were significantly associated with metastases outside the prostatic fossa. In patients with BCP, PSMA PET/CT imaging is warranted to guide salvage treatment strategies.
Advances in diagnostic imaging create opportunities for improved therapeutic targeting of cancer but conceptual thinking about radiotherapy target volume definition and dose-prescription is not ...keeping up. In this opinion paper we discuss how modern imaging can contribute to new concepts for radiotherapy dose-prescription and target volume definition illustrated by the example of head and neck cancer. These new insights have the potential to significantly reduce radiation associated toxicity and may have important impact on the combination of radiotherapy with systemic cancer therapies.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
In recent years, the possibility of adapting radiotherapy to changes in biological tissue parameters has emerged. It is hypothesized that early identification of radio-resistant parts of the tumor ...during treatment provides the possibility to adjust the radiotherapy plan to improve outcome. The aim of this systematic literature review was to evaluate the current state of the art of biological PET-guided adaptive radiotherapy, focusing on dose escalation to radio-resistant tumor.
A structured literature search was done to select clinical trials including patients with head and neck cancer of the oral cavity, oropharynx, hypopharynx or larynx, with a PET performed during treatment used to develop biological adaptive radiotherapy by: 1) delineation of sub-volumes suitable for adaptive re-planning; 2) in-silico adaptive treatment planning; or 3) treatment of patients with PET based dose escalated adaptive radiotherapy.
Nineteen articles were selected, 12 articles analyzing molecular imaging signal during treatment and 7 articles focused on biological adaptive treatment planning, of which two were clinical trials. Studied biological pathways include metabolism (FDG), hypoxia (MISO, FAZA and HX4) and proliferation (FLT).
In the development of biological dose adaptation in radiotherapy for head-neck tumors, many aspects of the procedure remain ambiguous. Patient selection, tracer selection for detection of the radio-resistant sub-volumes, timing of adaptive radiotherapy, workflow and treatment planning aspects are discussed in a clinical context.
•There is long-standing convention to irradiate almost all oropharyngeal cancer (OPC) bilaterally.•Contralateral regional failure (cRF) after unilateral RT of OPC is 2.4%•Involvement of the midline ...is the most significant prognosticator for cRF after unilateral RT.•Bilateral RT means an overtreatment in a substantial proportion of patients with lateralized OPC.•These results call for trials to expand the indications for unilateral RT in selected groups of OPC.
The head and neck region has rich regional lymphatic network, with a theoretical risk on contralateral metastasis from oropharyngeal cancer (OPC). There is a long-standing convention to irradiate the great majority of these tumors electively to both sides of the neck to reduce the risk of contralateral regional failure (cRF), but this can induce significant toxicity. We aimed to identify patient groups where elective contralateral irradiation may safely be omitted.
PubMed and EMBASE were searched for original full-text articles in English with a combination of search terms related to the end points: cRF in OPC primarily treated by radiotherapy only to the ipsilateral neck and identifying predictive factors for increased incidence of cRF. The data from the identified studies were pooled, the incidence of cRF was calculated and the correlation with different predictive factors was investigated.
Eleven full-text articles met the inclusion criteria. In these studies, 1116 patients were treated to the ipsilateral neck alone. The mean incidence of cRF was 2.42% (range 0–5.9%, 95% CI 1.6–3.5%). The incidence of cRF correlated only with T-stage (p=0.008), and involvement of midline (p=0.001). However, the significant correlation with T-stage can be explained by the very low incidence of cRF among T1 (0.77%), and disappeared when the incidence of cRF was compared between T2, T3,and T4 (p=0.344).
The incidence of cRF in patients with OPC is very low, with involvement of midline providing the most significant prognosticator. These results call for trials on unilateral elective irradiation in selected groups.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Prostate-specific membrane antigen (PSMA) positron emission tomography/computed tomography (PET/CT) is used for detection and (re)staging of prostate cancer. However, healthy salivary, seromucous, ...and lacrimal glands also have high PSMA-ligand uptake. This study aimed to describe physiologic PSMA-ligand uptake distribution characteristics in the head and neck to aid in PSMA PET/CT interpretation and to identify possible new clinical applications for PSMA-ligand imaging.
Thirty consecutive patients who underwent PSMA PET/CT for prostate cancer were evaluated. Tracer maximum standardized uptake values (SUVmax) in the salivary, seromucous, and lacrimal glands were determined visually and quantitatively. Overall and intraindividual variations were reported.
All gland locations had increased tracer uptake. The mean SUVmax ± standard deviation varied: parotid 12.3 ± 3.9; submandibular 11.7 ± 3.5; sublingual 4.5 ± 1.9; soft palate 2.4 ± 0.5; pharyngeal wall 4.3 ± 1.3; nasal mucosa 3.4 ± 0.9; supraglottic larynx 2.7 ± 0.7; and lacrimal 6.2 ± 2.2. The parotid had the largest overall variation in SUVmax (5.2-22.9), and the sublingual glands had the largest mean intraindividual difference (18.1%).
Major and minor salivary and seromucous glands consistently have high PSMA-ligand uptake. Minor gland locations can be selectively visualized by this technique for the first time. This provides potential new applications such as quantification of present salivary gland tissues and individualization of radiotherapy for head and neck cancer or lutetium-177-PSMA radionuclide treatment.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UL, UM, UPCLJ, UPUK, ZRSKP
Prostate cancer patients with locoregional lymph node disease at diagnosis (N1M0) still have a limited prognosis despite the improvements provided by aggressive curative intent multimodal ...locoregional external beam radiation therapy (EBRT) with systemic androgen deprivation therapy (ADT). Although some patients can be cured and the majority of patients have a long survival, the 5-year biochemical failure rate is currently 29-47%.
LuLu-PSMA-617 has shown impressive clinical and biochemical responses with low toxicity in salvage setting in metastatic castration-resistant prostate cancer. This study aims to explore the combination of standard EBRT and ADT complemented with a single administration of
LuLu-PSMA-617 in curative intent treatment for N1M0 prostate cancer. Hypothetically, this combined approach will enhance EBRT to better control macroscopic tumour localizations, and treat undetected microscopic disease locations inside and outside EBRT fields.
The PROQURE-I study is a multicenter prospective phase I study investigating standard of care treatment (7 weeks EBRT and 3 years ADT) complemented with one concurrent cycle (three, six, or nine GBq) of systemic
LuLu-PSMA-617 administered in week two of EBRT. A maximum of 18 patients with PSMA-positive N1M0 prostate cancer will be included. The tolerability of adding
LuLu-PSMA-617 will be evaluated using a Bayesian Optimal Interval (BOIN) dose-escalation design. The primary objective is to determine the maximum tolerated dose (MTD) of a single cycle
LuLu-PSMA-617 when given concurrent with EBRT + ADT, defined as the occurrence of Common Terminology Criteria for Adverse Events (CTCAE) v 5.0 grade three or higher acute toxicity. Secondary objectives include: late toxicity at 6 months, dosimetric assessment, preliminary biochemical efficacy at 6 months, quality of life questionnaires, and pharmacokinetic modelling of
LuLu-PSMA-617.
This is the first prospective study to combine EBRT and ADT with
LuLu-PSMA-617 in treatment naïve men with N1M0 prostate cancer, and thereby explores the novel application of
LuLu-PSMA-617 in curative intent treatment. It is considered likely that this study will confirm tolerability as the combined toxicity of these treatments is expected to be limited. Increased efficacy is considered likely since both individual treatments have proven high anti-tumour effect as mono-treatments.
ClinicalTrials, NCT05162573 . Registered 7 October 2021.
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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