Salivary Gland Cancer Patients Research Articles

Oncologic outcomes of the most prevalent major salivary gland cancers: retrospective cohort study from single center.

The preoperative diagnosis of salivary gland cancer (SGC) is crucial for the application of appropriate treatment, particularly involving the extension of the resection. Retrospective search of medical database identified 116 patients treated surgically with malignant tumors of salivary gland between 2010 and 2020. Analysis included the demographical data, clinical course, type of surgical and adjuvant treatment, histology type and margin status, perivascular invasion (LVI), perineural invasion (PNI), metastatic lymph nodes (LN). Facial nerve function, recurrence-free and overall survival were evaluated. Adequate statistics were used for data analysis. The final cohort included 63 SGC patients, with adenoid cystic carcinoma the most common pathological type (27%, n = 17), followed by adenocarcinoma (17.4% n = 11). T1 and T2 patients accounted for majority cases (n = 46). The lymph node metastases were confirmed with the histopathology in 31.7% (n = 20). Distant metastases were observed in 4.8% of cases (n = 3). 38% (n = 24) of SGC were treated selectively with surgery, 49.2% (n = 31) had postoperative radiotherapy and 15.9% (n = 10)-radio-chemotherapy. The final facial nerve function was impaired in 38% of patients. Mean overall survival (OS) for all patients was 108.7 (± 132.1) months, and was the most favorable for acinar cell carcinoma (118.9 ± 45.4) and the poorest for squamous cell carcinoma (44 ± 32). Cox regression analysis of disease-free survival and OS identified significant association only with patients' age over 65years, the hazard ratio of 7.955 and 6.486, respectively. The efficacy of treatment modalities for SGC should be verified with regard to the histopathological type, but also the patients' age should be taken into account.

Definitive Chemoradiotherapy for Salivary Gland Cancers

Surgical resection is the standard of care for salivary gland tumors of the head and neck. The role of radiotherapy is typically reserved for the adjuvant setting in those patients with high risk factors on surgical pathology. Surgical resection in some cases may lead to significant impairment in speech or swallowing due to location of the primary tumor. In other cases, patients may not be medically able to receive an oncologic resection. Our institution has developed a protocol for organ preservation for well-selected salivary gland malignancies. Here we report disease outcomes of salivary gland cancer patients treated with definitive chemoradiotherapy. We retrospectively reviewed all salivary gland cancer patients at our institution who received definitive chemoradiation from January 1990 to December 2019. Chemoradiation typically consisted of 4 to 6 alternating weekly cycles of paclitaxel (100 mg/m2 on d1), infusion 5-fluorouracil (600 mg/m2/d on d0-5), hydroxyurea (500 mg PO BID), and either 1.8 Gy or 2 Gy daily or 1.5 Gy twice-daily irradiation followed by a 9-day treatment break (TFHX). The Kaplan-Meier method was used to estimate rates of locoregional control (LRC), distant metastasis-free survival (DMFS), and overall survival (OS). Nineteen patients met eligibility criteria and were included for analysis. 53% of patients had adenoid cystic histology. Salivary duct, mucoepidermoid, acinic cell, and myoepithelial histologies each were represented by 10.5% of patients. About 26% of tumors were located in the nasopharynx, 21% in the base of tongue and 26% in the parotid. 74% of the patients were node negative and 53% of patients had stage IVA disease. T3 disease occurred in 26.3% while T4a and T4b disease occurred in 31.6% each. Median follow-up was 45.8 (IQR: 29-66) months. 47% of patients were treated using a twice daily approach, while 53% were treated with daily fractionation with a median dose of 72 Gy (IQR: 70-75). Three-year locoregional control (LRC), distant-metastasis free survival (DMFS), and overall survival (OS) were 93%, 76%, and 81% respectively. Eight of nine distant failures had T4a/T4b disease. Accounting for competing risk of death, local failure was 5.6% at three years. The most common acute complications were grade 2-3 mucositis (74%) and skin toxicity (47%). One patient discontinued chemoradiation due to severe hand foot mouth syndrome. 42% of patients had late toxicity of xerostomia. Promising organ preservation is seen with concurrent chemoradiation for salivary gland cancer patients. Further prospective study of organ preservation in salivary gland cancers is warranted.

Retrospective analysis of genetically matched therapies in salivary gland cancer entities using a real-world database in a tertiary salivary gland cancer expertise center.

6098 Background: Salivary gland cancer (SGC) is a rare cancer and includes twenty-two different entities. In the Radboudumc SGC expertise center, a real-word database was set up to uniformly collect data of SGC subtypes. More than 500 SGC patients have been enrolled and collection of data for 261 patients is currently completed. Here, we describe the retrospective analysis of genetic aberrations found in different SGC entities and the treatment of selected recurrent/metastatic (R/M) patients with genetically matched therapies (GMT). Methods: All SGC patients in the SGC registry of Radboudumc between 2017 and 2022 whose tumors underwent next generation sequencing (NGS) and/or gene fusion analysis within standard of care or clinical trial were included in this analysis. Both primary tumor specimen and metastatic tissue have been used for molecular analyses. GMT was given in basket trials or on basis of compassionate use for clinically relevant genetic aberrations that are considered actionable nowadays. Results: NGS and/or gene fusion analysis data was available for 162 out of 261 patients, and most frequently in salivary duct carcinoma (SDC) patients (82/162). The number of patients with genetic aberrations differed between SGC entities. In 112 patients at least one genetic aberration and/or gene fusion was detected regardless of whether the target was druggable. Ninety-three patients out of 112 patients had R/M disease. Both a gene fusion and one or more mutations were found in six patients (adenoid cystic carcinoma [AdCC], n = 3; SDC, n = 2; and secretary carcinoma [SC], n = 1;). Depending on the SGC subtype, in 14.3 – 100% of the R/M cases with genetic aberrations and/or gene fusions a GMT was started (SDC, 14/60; AdCC, 3/21; SC, 2/2; mucoepidermoid carcinoma, 2/4). The most given GMT among patients were monoclonal antibodies and tyrosine kinase inhibitors (TKI), respectively in nine and eleven patients, moreover immunotherapy was started in one patient. For example, eight SDC patients were treated with ERBB2 targeting agents (4/8 mutations; 4/8 copy number variants in ERBB2), showing a complete response in three patients. Additionally, one partial response and two stable diseases were observed, two patients were lost of follow-up. Two SC patients treated with a TKI based on the presence of the ETV6- NTRK gene fusion showed radiologically a partial response. Conclusions: In 69% of the SGC patients at least one genetic aberration and/or gene fusion was found, and in 23% of the R/M cases GMT was administered. Response differs between entities and GMT; a complete response was achieved after initiation of GMT in several patients. These data justify the use of NGS and gene fusion analysis in all salivary gland cancer entities, notably in subtypes lacking standard systemic therapies as this could offer other therapeutic options.

177Lu-PSMA radioligand therapy for patients with recurrent/metastatic (R/M) salivary gland cancer (SGC): A phase II pilot study.

6099 Background: New treatments are warranted due to limited systemic treatment options for SGC patients (pts). Gallium [68Ga]Ga prostate-specific membrane antigen (PSMA) PET imaging results in SGC pts have demonstrated PSMA expression of SGC and thus indicated that PSMA radionuclide therapy may be a useful option, especially in the case of adenoid cystic carcinoma (AdCC) and salivary duct carcinoma (SDC) subtypes. Therefore, this study (EudraCT number 2019-003857-27) evaluated the safety and efficacy of PSMA-targeted radionuclide therapy in AdCC and SDC pts. Methods: This was a single-center, single-arm, phase II pilot study. R/M AdCC (n = 10) and SDC (n = 5) pts with sufficient PSMA tracer uptake on [68Ga]Ga-PSMA PET imaging, i.e., ≥1 lesion ≥1.5cm with PSMA expression above mean liver level, were treated with 2-4 cycles of 7.4 GBq [177Lu]Lu-PSMA-I&T, with an interval of 6±1 weeks. Baseline imaging was repeated for evaluation 4 weeks after cycle 2; in case of progressive disease (PD) per RECIST 1.1 the treatment was discontinued; otherwise, pts received the full treatment (4 cycles). All pts received whole body post-therapeutic imaging after 1, 24, 48, 72 h and 7d after each cycle. The primary endpoint was safety. Secondary endpoints include the objective response rate, progression-free survival (PFS), and overall survival (OS). Results: Between 6-2020 and 2-2023, 15 AdCC pts and 10 SDC pts were screened for eligibility. Five AdCC pts and 8 SDC pts were screen failures due to insufficient PSMA expression in 11 pts (AdCC n = 4; SDC n = 7) or due to brain metastases in 2 pts (AdCC n = 1; SDC n = 1). Ten AdCC and 2 SDC pts received at least one cycle of 7.4 GBq [177Lu]Lu-PSMA-I&T. The most observed adverse events (grade 1-2) included: nausea (75%), dry mouth (75%), fatigue (67%), and anemia (58%). Two pts (17%) developed grade 3 toxicity; lymphocytopenia (n = 1) and hyponatremia (n = 1). No grade 4-5 toxicities were observed. Two pts (AdCC n = 1; SDC n = 1) received only 1 treatment cycle due to early PD. The interim-treatment evaluation resulted in the discontinuation of treatment after 2 cycles in an additional 3 AdCC and the second SDC pts due to PD. Six AdCC pts received the full treatment (4 cycles); no responses were observed; 3 pts (75%) showed stable disease of more than 3 months after treatment completion (5, 15 and 21 months); 3 pts showed PD at 3 months after treatment completion. Median PFS in 10 AdCC pts was 6.7 months (95%CI: 0.0-15.1); OS was not reached after a median follow-up of 11.9 months. Conclusions: [177Lu]Lu-PSMA-I&T treatment in SGC pts is well-tolerated. The efficacy in AdCC was limited; only stable disease was achieved in 3 out of 10 pts. In most screened SDC pts, PSMA expression was insufficient to undergo [177Lu]Lu-PSMA-I&T treatment; the 2 SDC pts included showed early PD. Dosimetry analyses will be performed to calculate the delivered radiation doses to organs at risk as well as tumor lesions. Clinical trial information: EUCTR2019-003857-27.

Prognostic effects of previous cancer history on patients with major salivary gland cancer.

To explore the prognostic effects of previous cancer history on patients with major salivary gland cancer (SGC). SGC patients with (sec-SGC) and without (one-SGC) a previous cancer from the SEER database were identified. Cox proportional hazards regression (CoxPH) models were used to compare the prognosis between sec-SGC and one-SGC patients. Subgroup analyses for sec-SGC patients by gender, previous cancer types, previous cancer histology, and cancer diagnosis interval (CDI) were performed. Two CoxPH models were constructed to distinguish sec-SGC patients with different prognostic risks. 9098 SGC patients were enrolled. Overall, sec-SGC patients (adjusted HR [aHR]=1.26, p < 0.001), especially those with a CDI ≤ 5 years (aHR=1.47, p < 0.001), had worse overall survival (OS) than one-SGC patients. In subgroup analysis, only sec-SGC patients with a previous head and neck cancer who were female (aHR=2.38, p=0.005), with a CDI ≤ 5 years (aHR=1.65, p=0.007) or with a previous squamous cell carcinoma (aHR=6.52, p < 0.001) had worse OS. Our models successfully differentiated all sec-SGC patients into high-, intermediate- and low-risk groups with different prognosis. Sec-SGC patients with different previous cancer types, gender, CDI and previous cancer histology had varied prognosis. The models we constructed could help differentiate the prognosis of sec-SGC patients with different risks.

Kidney absorbed radiation doses for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T determined by 3D clinical dosimetry.

For prostate-specific membrane antigen-directed radioligand therapy (PSMA-RLT), [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T are the currently preferred compounds. Recent preclinical studies suggested ~30x higher kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T compared to [ 177 Lu]Lu-PSMA-617, which may lead to an increased risk of kidney toxicity. We performed two single-centre, prospective dosimetry studies with either [ 177 Lu]Lu-PSMA-617 or [ 177 Lu]Lu-PSMA-I&T, using an identical dosimetry protocol. We evaluated the absorbed doses of both 177 Lu-labelled radioligands in human kidneys. 3D SPECT/computed tomography (CT) imaging of the kidneys was performed after PSMA-RLT in cancer patients with PSMA-positive disease and an adequate glomerular filtration rate (≥50 mL/min). Ten metastatic hormone-sensitive prostate cancer patients (mHSPC) were treated with [ 177 Lu]Lu-PSMA-617 and 10 advanced salivary gland cancer (SGC) patients were treated with [ 177 Lu]Lu-PSMA-I&T. SPECT/CT imaging was performed at five timepoints (1 h, 24 h, 48 h, 72 h, and 168 h post-injection). In mHSPC patients, SPECT/CT imaging was performed after cycles 1 and 2 (cumulative activity: 9 GBq) and in SGC patients only after cycle 1 (activity: 7.4 GBq). Kidney absorbed dose was calculated using organ-based dosimetry. The median kidney absorbed dose was 0.49 Gy/GBq (range: 0.34-0.66) and 0.73 Gy/GBq (range: 0.42-1.31) for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T, respectively (independent samples t test; P = 0.010). This study shows that the kidney absorbed dose for [ 177 Lu]Lu-PSMA-617 and [ 177 Lu]Lu-PSMA-I&T differs, with a ~1.5x higher median kidney absorbed dose for [ 177 Lu]Lu-PSMA-I&T. This difference in the clinical setting is considerably smaller than observed in preclinical studies and may not hamper treatments with [ 177 Lu]Lu-PSMA-I&T.

Pre-treatment quality of life in patients with salivary gland cancer in comparison with those of head and neck cancer patients.

Salivary gland cancer (SGC) is a rare malignant tumor arising from the salivary glands, with a variety of clinical and biological behaviors different from head and neck cancer (HNC). Because of the rarity of SGC, there are limited data on pre-treatment quality of life (QoL). Therefore, we evaluated the pre-treatment QoL in SGC patients by stage and compared it with that of HNC patients. From a prospective registry of HNC patients (2016-2020), we selected 225 patients with SGC, and 912 patients with oral cavity (OC) and oropharyngeal cancer (OPC) who were diagnosed in the same period as the HNC control group. The European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and HNC-Specific Module (H&N35) were used to assess QoL. SGC patients had a statistically better baseline QoL (69.8 vs. 64.0), emotional (82.1 vs. 78.8), cognitive (92.0 vs. 88.7), and social function (86.3 vs. 80.5), and fewer symptoms than HNC patients. The estimated average QoL differences between SGC patient diagnosed at stages I and IV was -12.9. Especially, advanced-stage of tumors was associated with much lower role functioning and emotional functioning scores in SGC patients, compared to those in HNC patients, among females and of younger age. Although the overall QoL score was higher in SGC patients than in HNC patients, specific domains were significantly affected in SGC patients according to the tumor stage. Females and those of younger age were more affected by severity of disease in SGC. ClinicalTrials.gov Identifier NCT02546895.

Development and characterization of patient-derived salivary gland cancer organoid cultures

ObjectiveThree-dimensional organoid cell cultures have been established for a variety of human cancers. For most rare cancers, including salivary gland cancer (SGC), these models are lacking, despite the great unmet need to study cancer biology in these diseases. Therefore, we aimed to develop patient-derived organoid (PDO) models for different subtypes of SGC. MethodsTumor samples of SGC patients were processed and embedded in Matrigel. Successful PDOs (expandable > 1*106 cells) were phenotypically characterized using immunohistochemistry (IHC) and genotypically by gene fusion analysis and by targeted and whole-exome sequencing. Successfully established PDOs were subjected to small-scale drug screening. ResultsOut of 37 attempts, 7 viable short-term PDOs were established (19 % success rate; 3 salivary duct carcinoma, 3 adenoid cystic carcinoma and 1 mucoepidermoid carcinoma). Each PDO showed close phenotypical mimicry to parental tissue. Genotypic characterization revealed that in each PDO > 97.6 % of all COSMIC annotated variants and all MYB, MYBL1 and NFIB gene rearrangements were retained. Drug screening was proven feasible in all PDOs. ConclusionWe present the first comprehensively characterized short-term SGC PDO models for three subtypes of SGC with close phenotypic and genotypic resemblance to parental tissue, which can be used for drug screening applications.

Identification of Fusion Genes and Targets for Genetically Matched Therapies in a Large Cohort of Salivary Gland Cancer Patients.

Simple SummarySalivary gland cancer (SGC) is a rare and heterogeneous cancer for which limited treatment options are available in the palliative treatment setting. Characterization of the SGC genetic landscape to identify actionable aberrations is therefore important. This research aimed to comprehensively assess the prevalence of various types of actionable aberrations, including gene fusions, in a large cohort of patients with different SGC subtypes. The combined approach using RNA- and DNA-based targeted next-generation sequencing panels revealed the presence of gene fusions in half of the cases, including several fusions not previously described in SGC. Targets for genetically matched therapies were identified in 28.3–81.8% of cases, depending on the SGC subtype (overall 53.7% of the cases). This highlights the potential of molecular diagnostics to select systemic treatment in SGC.Introduction: Salivary gland cancer (SGC) is a rare cancer for which systemic treatment options are limited. Therefore, it is important to characterize its genetic landscape in search for actionable aberrations, such as NTRK gene fusions. This research aimed to identify these actionable aberrations by combining NGS-based analysis of RNA (gene fusions) and DNA (single and multiple nucleotide variants, copy number variants, microsatellite instability and tumor mutational burden) in a large cohort of SGC patients. Methods: RNA and DNA were extracted from archival tissue of 121 patients with various SGC subtypes. Gene fusion analysis was performed using a customized RNA-based targeted NGS panel. DNA was sequenced using a targeted NGS panel encompassing 523 cancer-related genes. Cross-validation of NGS-based NTRK fusion detection and pan-TRK immunohistochemistry (IHC) was performed. Results: Fusion transcripts were detected in 50% of the cases and included both known (MYB-NFIB, MYBL1-NFIB, CRTC1-MAML2) and previously unknown fusions (including transcripts involving RET, BRAF or RAD51B). Only one NTRK fusion transcript was detected, in a secretory carcinoma case. Pan-TRK IHC (clone EPR17341) was false positive in 74% of cases. The proportion of patients with targets for genetically matched therapies differed among subtypes (salivary duct carcinoma: 82%, adenoid cystic carcinoma 28%, mucoepidermoid carcinoma 50%, acinic cell carcinoma 33%). Actionable aberrations were most often located in PIK3CA (n = 18, 15%), ERBB2 (n = 15, 12%), HRAS and NOTCH1 (both n = 9, 7%). Conclusions: Actionable genetic aberrations were seen in 53.7% of all SGC cases on the RNA and DNA level, with varying percentages between subtypes.

Machine Learning-Based Predictor for Treatment Outcomes of Patients With Salivary Gland Cancer After Operation

Background and Objectives The purpose of this study was to analyze the survival data of salivary gland cancer (SGCs) patients to construct machine learning and deep learning models that can predict survival and use them to stratify SGC patients according to risk estimate.Subjects and Method We retrospectively analyzed the clinicopathologic data from 460 patients with SGCs from 2006 to 2018.Results In Cox proportional hazard (CPH) model, pM, stage, lymphovascular invasion, lymph node ratio, and age exhibited significant correlation with patient’s survival. In the CPH model, the c-index value for the training set was 0.85, and that for the test set was 0.81. In the Random Survival Forest model, the c-index value for the training set was 0.86, and that for the test set was 0.82. Stage and age exhibited high importance in both the Random Survival Forest and CPH models. In the deep learning-based model, the c-index value was 0.72 for the training set and 0.72 for the test set. Among the three models mentioned above, the Random Survival Forest model exhibited the highest performance in predicting the survival of SGC patients.Conclusion A survival prediction model using machine learning techniques showed acceptable performance in predicting the survival of SGC patients. Although large-scale clinical and multicenter studies should be conducted to establish more powerful predictive model, we expect that individualized treatment can be realized according to risk stratification made by the machine learning model.

Oncological outcomes of patients with salivary gland cancer treated with surgery and postoperative intensity-modulated radiotherapy: a retrospective cohort study.

Salivary gland cancer (SGC) is relatively rare and constitutes a variety of histological subtypes. Previously published studies of SGC patients suggest that postoperative radiation using conventional radiotherapy (RT) or 3-dimensional (3D) conformal radiotherapy may have led to suboptimal oncological outcomes. We identified 60 patients with major SGC treated with surgery followed by postoperative intensity-modulated radiotherapy (IMRT). Data for overall survival (OS), progression-free survival (PFS), locoregional relapse-free survival (LRRFS), distant metastasis-free survival (DMFS), prognostic factors, and treatment-related toxicities were analyzed. Survival was analyzed using the Kaplan-Meier method and compared using the log-rank test. With a median follow-up of 55.5 months, based on Kaplan-Meier analyses, the OS and PFS rates for SGC patients at 3, 5, and 10 years were 90.7%, 85.1%, and 85.1% and 80.1%, 72.7%, and 63.1%, respectively. The LRRFS and DMFS rates at 3, 5, and 10 years were 87.4%, 82.1%, and 82.1% and 85.3%, 78.4%, and 66.1%, respectively. In multivariable analysis (MVA), the node stage (N stage) was an independent predictor of PFS [P=0.047; hazard ratio (HR) =0.089]. A positive margin was a significant prognostic factor for PFS (P=0.036; HR =4.086), LRRFS (P=0.026; HR =5.064), and DMFS (P=0.011; HR =6.367). Major nerve involvement was significantly correlated with PFS (P=0.034; HR =2.394) and DMFS (P=0.008; HR =2.115). The interval from surgery to radiotherapy predicted PFS (P=0.036; HR =3.934) and DMFS (P=0.012; HR =6.231). Adenoid cystic carcinoma (ACC) was the most common histology (n=21; 35%). For ACC, the 5-year OS, PFS, LRRFS, and DMFS were 100%, 67.7%, 76.2%, and 90.2%, respectively. The most common acute toxicities were mucositis and dermatitis, and xerostomia was the most common late adverse event. Lung metastasis was the most common pattern of distant failure. N stage, positive margin, major nerve involvement, and interval from surgery to radiotherapy were important factors associated with PFS, LRRFS, and DMFS. Postoperative IMRT leads to improved survival for SGC patients, with acceptable toxicities.

Targeted Therapy, Chemotherapy, Immunotherapy and Novel Treatment Options for Different Subtypes of Salivary Gland Cancer.

Surgical resection remains the first line treatment for salivary gland cancer (SGC). In the case of locally advanced disease, surgery is followed by adjuvant radiotherapy. Surgical resection should be favored in resectable locoregional recurrent disease as well, and even the complete resection of all distant oligometastases has clinical benefit for the patients. For inoperable and disseminated metastatic disease, a multitude of systemic therapies including chemotherapy, targeted therapy, and immunotherapy are available. In this review, the current therapeutic options for inoperable recurrent or metastatic SGCs are summarized. Systemic treatment can achieve prolonged progression-free and overall survival, while the overall prognosis remains poor. Current clinical trials include only a limited number of patients and mostly combine different histologic subtypes. Additionally, no randomized controlled trial comparing different therapeutic options has been performed. In the future, further studies with a larger patient cohort and ideally only one histologic subtype are needed in order to improve the outcome for SGC patients. However, this may be difficult to accomplish due to the rarity and diversity of the disease. Additionally, molecular analyses need to be performed routinely in order to individualize treatment and to go one step further towards precision medicine.

Abstract 1363: Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer

Abstract Background Cabozantinib is approved for treatment of renal cell cancer (RCC) in a starting dose of 60 mg. However, in the registration studies dose reductions were needed in 46-62% of patients due to toxicity. Improved clinical efficacy of cabozantinib was observed in RCC patients with an average exposure of &amp;gt; 750 ug/L. Data about cabozantinib pharmacokinetics in patients routinely treated with this drug is scarce, while treatment is challenging due to toxicity. Therefore, we explored the cabozantinib exposure in patients with two different tumour types in our clinic. Methods Clinical data and cabozantinib trough concentrations (Cmin) were collected from all patients treated with cabozantinib with at least one measured Cmin at steady state in our clinic between Jan 2018 - Aug 2020. We included salivary gland cancer (SGC) patients treated in a phase II study and RCC patients from our outpatient clinic. Geometric mean (GM) Cmin at the start dose, at 40 mg and at best tolerated dose (BTD) were compared between the two tumour types. Results In total 47 patients were included. All patients with SGC (n=22) started with 60 mg, while 13 of 25 patients with RCC started with 40 mg. GM Cmin level at the start dose was 1350 µg/L (95% CI 1182-1781) vs. 689 µg/L (95% CI 576-823) (P&amp;lt;.001) for patients with SGC and RCC, respectively. When dose-normalized to 40 mg, SGC patients had a significantly higher cabozantinib exposure compared to RCC patients (GM Cmin 968 µg/L (95% CI 788-1188) vs. 676 µg/L (95% CI 571-799)(P=.007). A higher cabozantinib GM Cmin level was observed in female compared to male patients. Dose reductions due to toxicity were needed in 91% and 60% of patients with SGC and RCC, respectively. Median BTD was 25 mg for SGC patients and 40 mg for RCC patients. GM Cmin at BTD were comparable between the SGC group and the RCC group, i.e. 692 µg/L (95% CI 582-822) vs. 576 µg/L (95% CI 493-673) (P=.1), respectively. At BTD, 64% of SGC patients and 80% of RCC patients had an exposure below the proposed target of &amp;gt;750 ug/L. Conclusion Unexpectedly, cabozantinib levels were significantly higher in patients with SGC compared to those with RCC at the dose of 40 mg. However, cabozantinib levels at BTD were comparable between patients with SGC and RCC. At BTD, the majority of patients did not reach the target of &amp;gt;750 µg/L. For most patients with RCC, the cabozantinib level at BTD corresponded to a dose of 40 mg. Therefore, 40 mg instead of 60 mg as a starting dose followed by dose-adjustment based on exposure and tolerability may be preferred in patients with RCC. Although cabozantinib is not registered for SGC, an even lower starting dose of 20 mg/day may be required in these patients based on cabozantinib levels at BTD. Future studies should focus on identifying an optimal and tolerable exposure-response target value for cabozantinib and elucidate factors that contribute to the differences in exposure, in order to individualise and improve treatment. Citation Format: Stefanie D. Krens, Wim van Boxtel, Maike J. Uijen, Frank G. Jansman, Ingrid M. Desar, Sasja F. Mulder, Carla M. van Herpen, Nielka P. van Erp. Exposure-toxicity analysis of cabozantinib in patients with salivary gland cancer and renal cell cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 1363.

Incidence and survival of salivary gland cancer in children and young adults in Denmark: A nation-wide study for the period 1990–2015

ObjectivesThe aim of this study was to evaluate incidence and survival of children and young adults with salivary gland cancer (SGC) in Denmark during the period 1990–2015. MethodWe included all patients aged 0–24 years registered with primary SGC in the Danish Cancer Registry, the Danish Pathology Data Bank, or the DAHANCA database during 1990–2015. Patients were divided in two age-groups: children (0–17 years) and young adults (18–24 years). Incidence rates, overall survival (OS), and recurrence free survival (RFS) was evaluated in relation to age-group, sex, tumor location, tumor histology, and T-, N-, and M-classification. ResultsA total of 70 SGC patients between 0 and 24 years (67% female, n = 47) were included. Thirty-six were children at time of diagnosis, and 34 were young adults. The incidence was higher among young adults compared to children (0.29 vs. 0.11 per 100.000) and showed no significant change during the study period. There were no differences in the distribution of sex, tumor location, or tumor histology between children and young adults. The total 5 and 15-year survival rates were 97.1% and 91.7% for OS, and 97.1% and 83.1% for RFS. The survival rates showed no significant differences according to age-groups, sex, tumor location, or tumor histology. Patients diagnosed in stage T4 had significantly worse OS and RFS. ConclusionThe incidence of SGC among children and young adults in Denmark was low and stable in the period 1990–2015. The overall survival was very high, demonstrating the excellent prognosis for children and young adults with SGC.

Prediction of Recurrence by Machine Learning in Salivary Gland Cancer Patients After Adjuvant (Chemo)Radiotherapy.

To investigate survival outcomes and recurrence patterns using machine learning in patients with salivary gland malignant tumor (SGMT) undergoing adjuvant chemoradiotherapy (CRT). Consecutive SGMT patients were identified, and a data set included nine predictor variables and a dependent variable [disease-free survival (DFS) event] was standardized. The open-source R software was used. Survival outcomes were estimated by the Kaplan-Meier method. The random forest approach was used to select the important explanatory variables. A classification tree that optimally partitioned SGMT patients with different DFS rates was built. In total, 54 SGMT patients were included in the final analysis. Five-year DFS was 62.1%. The top two important variables identified were pathologic node (pN) and pathologic tumor (pT). Based on these explanatory variables, patients were partitioned in three groups, including pN0, pT1-2 pN+ and pT3-4 pN+ with 26%, 38% and 75% probability of recurrence, respectively. Accordingly, 5-year DFS rates were 73.7%, 57.1% and 34.3%, respectively. The proposed decision tree algorithm is an appropriate tool to partition SGMT patients. It can guide decision-making and future research in the SGMT field.

Metastatic salivary gland carcinoma: A role for stereotactic body radiation therapy? A study of AIRO-Head and Neck working group.

The role of radiotherapy (RT) for oligometastases is currently established in different oncological settings but data on salivary gland cancer (SGC) are lacking. We evaluated the role of RT in oligometastatic SGC patients, focusing on stereotactic body radiation therapy (SBRT). We performed a retrospective, multicentric study of oligometastatic SGC treated with palliative RT or SBRT. Endpoints included response evaluation and local control (LC). Between 2006 and 2016, 64 patients were collected from 9 Italian Cancer Centers, on behalf of the Italian Association of Radiotherapy and Clinical Oncology (AIRO) Head and Neck Working Group. 37 patients (57.8%) were suffering from adenoid cystic carcinoma (ACC) and 27 patients (42.2%) had non-ACC. Thirty-four patients underwent palliative RT (53,1%), and 30 received SBRT (46,9%). Most common metastatic sites were bone for palliative RT and lung for SBRT. Among patients treated with SBRT, an objective response or a stability was observed in all treated lesions. After a median follow-up of 29.2months (range 2.3-117.1), LC at 12months was 57.5% for patients treated with SBRT and was higher in ACC subgroup. We confirmed the potential role of SBRT in the management of oligometastatic SGC patients to control limited burden of disease considering the absence of effective systemic therapies.

Treatment outcomes of elderly salivary gland cancer patients undergoing radiotherapy – Results from a large multicenter analysis

Background and purposeTo evaluate oncological outcomes and treatment-related toxicities of elderly salivary gland cancer patients undergoing (chemo)radiotherapy. Material and methodsLocal/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) of elderly patients ≥ 65 years with primary salivary gland cancers undergoing (chemo)radiotherapy between 2005 and 2020 at three tertiary cancer centers were calculated. The impact of clinicopathological and treatment parameters on outcomes were analyzed, and acute and chronic toxicities were quantified. Results288 elderly salivary gland cancer patients were included in this multicenter analysis, and their median LRC, PFS and OS amounted to 113, 39 and 75 months, respectively. Age, performance status, comorbidities, definitive vs. adjuvant (chemo)radiotherapy as well as locally/locoregionally advanced cancers and distant metastases correlated with reduced outcomes in elderly salivary gland patients. Patients receiving dose-escalated radiotherapy (total doses > 70 GyEQD2) with carbon ion boost radiation resulted in improved LRC, but no improvements in PFS or OS. Concomitant chemoradiotherapy did not improve treatment outcomes in elderly salivary gland carcinoma patients. Radiotherapy of elderly salivary gland cancer patients resulted in moderate higher-grade toxicities despite dose escalation with 70 (24.3%) and 48 patients (16.7%) experiencing acute and chronic grade 3 toxicities, respectively. No grade 4/5 toxicities were observed in this patient cohort. ConclusionData from the largest multicenter analysis of elderly salivary gland cancer patients undergoing (chemo)radiotherapy demonstrate favorable LRC and tolerable toxicity rates. Decision-making for these vulnerable patients should be based on patient performance rather than chronological patient age.

Radiation-induced toxicities and outcomes after radiotherapy are independent of patient age in elderly salivary gland cancer patients: results from a matched-pair analysis of a rare disease

PurposeThis study analyzed survival and toxicity after (chemo)radiotherapy for primary salivary gland cancer patients aged ≥ 65 years and compared these results with younger patients using a matched-pair analysis.MethodsTwenty-nine elderly patients with primary salivary gland carcinomas treated with (chemo)radiotherapy from 2008 to 2020 at University of Freiburg Medical Center were analyzed for oncological outcomes and therapy-associated toxicities. Local/locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan–Meier method, and the influence of clinical parameters on patient outcomes was assessed. A matched-pair analysis was performed after matching with patients < 65 years.ResultsNine patients (31.0%) received definitive (chemo)radiotherapy, and 20 patients (69.0%) were treated in the adjuvant setting. 2-year LRC, PFS and OS ranged at 82.4%, 53.7% and 71.8%, respectively. Smoking (HR 3.980, p = 0.020), reduced performance status (HR 3.735, p = 0.016) and higher comorbidity burden (HR 4.601, p = 0.005) correlated with inferior OS. Using a matched-pair analysis with younger patients, elderly patients exhibited a trend towards reduced OS (HR 3.015, p = 0.065), but not PFS (HR 1.474, p = 0.371) or LRC (HR 1.324, p = 0.633). Acute and chronic grade 3 toxicities occurred in 31.0% and 12.5% of elderly patients, respectively, and the matched-pair analysis revealed no significant differences between age groups regarding treatment-related toxicities.ConclusionTreatment-related toxicities as well as LRC and PFS were comparable for salivary gland cancer patients undergoing radiotherapy. Therefore, concerns for more pronounced toxicities or reduced local/locoregional response rates should not guide treatment decisions in affected elderly patients.

A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients.

6529 A phase II study on the efficacy and toxicity of cabozantinib in recurrent/metastatic salivary gland cancer patients. Background: Because c-MET and VEGFR are often overexpressed in salivary gland cancer (SGC), this study evaluated the efficacy and safety of cabozantinib in recurrent/metastatic (R/M) SGC pts. Methods: A single center, single arm, phase II study was conducted. Immunohistochemical c-MET positive (H-score ≥10) R/M SGC pts were included in 3 cohorts: adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and other SGCs. Objective growth or complaints due to the disease were required before inclusion in the ACC and other SGC cohort. No prior systemic treatments were required. Pts started 60 mg cabozantinib tablets OD. Primary endpoint was the objective response rate (ORR). A Simon two-stage design was used. In case of ≥1 objective response in the first 9 pts/cohort, 8 additional pts would be included in the cohort. Results: In total 25 pts were included from Sep. 2018 until premature closure due to severe toxicity in Nov. 2019. Median age was 56 years (range 49-72), prior treatments included: primary tumor resection ( n=19), radiotherapy ≥50Gy ( n=24), systemic therapy ( n=10; adjuvant in 2 pts, palliative in 8 pts). Six pts had grade 3 ( n=4), grade 4 ( n=1), or grade 5 ( n=1) wound/fistula complications, occurring at a median of 7.2 mths on cabozantinib (range 2.1-12.8). This resulted in a severe wound complication rate of 32% in 19 pts on treatment for ≥2 mths. Remarkably, 4 out of 6 pts developed this complication in the area exposed to high-dose Rx; 2/4 had a pre-existing fistula in this area. Median interval between Rx and start of cabozantinib was 71.3 mths (range 10.6-94.7). Other grade ≥3 adverse events in &gt;1 pt were: hypertension (5 pts), diarrhoea (2 pts) and dehydration (2 pts). Current median follow-up is 6.8 mths. The ORR was 6% (1/17 pts) in the ACC cohort, 20% (1/5 pts) in the SDC cohort, and 0% (0/3 pts) in other SGC pts; median PFS is 12.6 mths (95% CI 6.8 – 18.4 mths), 9.0 mths (insufficient events for 95% CI), and 6.9 mths (95% CI 0 – 15.2 mths), respectively. Median OS is not reached in any cohort. Conclusions: This phase II study on cabozantinib in R/M SGC pts demonstrated severe wound and fistula complications in 32% of pts on treatment for ≥2 mths, mostly (4/6 pts) within the radiotherapy field. Because of this toxicity the study was closed prematurely. Furthermore, cabozantinib showed minimal clinical activity in SGC pts. Research funding: Ipsen Pharmaceuticals Clinical trial information: NCT03729297 .

Positive lymph node number and extranodal extension for predicting recurrence and survival in patients with salivary gland cancer.

This study compared our proposed N classification including the addition of the number of positive lymph node (LN+) and extranodal extension (ENE) with the current and previous American Joint Committee on Cancer (AJCC) N classifications in salivary gland cancer (SGC). This study involved 172 SGC patients who underwent surgery. Cox proportional hazard regression analyses were used to identify factors associated with overall survival (OS) and disease-free survival (DFS). In multivariate analyses, LN+ number, LN ratio, and ENE were associated with OS and DFS outcomes (all P < .05). Our new N classification proposed three categories: N0 (0 LN+), N1 (1 LN+), and N2 (≥2 LN+ or ENE). The C-index of our N classification showed improvement in OS prediction (0.768) compared with the AJCC seventh (0.743) and eighth (0.756) edition N classifications. Our proposed N classification incorporating LN+ number and ENE may improve prediction of post-treatment survival and recurrence in patients with SGC.