Role of surgery to the primary tumor in metastatic anaplastic thyroid carcinoma: pooled analysis and SEER-based study.

PURPOSE: Anaplastic thyroid carcinoma (ATC) is an orphan disease with a fatal outcome. Surgery to the primary tumor in metastatic ATC is controversial. Determination of specific surgical techniques may help facilitate local control and, hence, beneficial overall and disease-specific survival. METHODS: Using individualized patient data derived from our systematic review of literature and our single center study (n = 123), conducting a Surveillance, Epidemiology, and End Results register (SEER)-based study (n = 617) we evaluated surgery, its combination with systemic and local therapies in metastatic ATC. RESULTS: Pooled cohort study showed surgery (p < 0.001), RT ≥ 30 Gy (p < 0.001), ChT (p < 0.001) and multimodal treatment (p = 0.014) to result in improved OS univariately. In the multivariate analysis, surgery (1.997 [1.162-3.433], p = 0.012) and RT ≥ 30 Gy (1.877 [1.232-2.843], p = 0.012) were independent predictors for OS. In SEER-based study of patients undergoing any tumor-directed treatment (n = 445) total thyroidectomy (p = 0.031), administration of ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS univariately. On the multivariate analysis, debulking surgery was an independent predictor for a worse outcome (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whereas RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002). Among operated patients from SEER register total thyroidectomy (p = 0.031), ChT (p = 0.007), RT (p < 0.001), combination of surgery and RT ± ChT (p < 0.001) and multimodal treatment (p < 0.001) correlated with an improved DSS in the univariate analysis, whereas debulking surgery was inversely correlated with the DSS (p < 0.001). On the multivariate analysis, debulking surgery was an independent predictor for a worse DSS (HR 0.535, 95%CI 0.332-0.862, p = 0.010), whilst RT administration correlated with a longer DSS (HR 2.316, 95%CI 1.362-3.939, p = 0.002). CONCLUSIONS: Surgery to the primary tumor with the aim of R0/R1 resection, but not debulking, is associated with a significant OS and DSS benefit even in systemically metastasized disease.

[Retroperitoneal soft tissue sarcoma: role of radiotherapy]. / Retroperitoneale Weichgewebssarkome: Stellenwert der Radiotherapie.

BACKGROUND: Retroperitoneal soft tissue sarcomas (RPS) include tumors of mesenchymal origin with overall well-defined histological subtypes and heterogenic prognosis. For the first time with the publication of the STRASS study, which investigated the value of neoadjuvant radiotherapy in primary RPS, there is phase III evidence for the use of radiotherapy. OBJECTIVE: The primary objective of the present article is to present the role of neoadjuvant radiotherapy in RPS since the publication of the STRASS study. MATERIAL AND METHODS: We performed a non-systematic literature search. The results of retrospective and observational studies were compared to those of the STRASS study. RESULTS: In the two of the largest analyses, the surveillance, epidemiology, and end results program (SEER) and the American National Cancer Database (NCDB), an improvement in overall survival due to radiotherapy in RPS could be shown. In contrast to these results, there was no significant improvement in 3­year abdominal recurrence-free survival in the STRASS study. There was solely a trend to improved abdominal recurrence-free survival in initially unplanned subgroup analyses for patients with liposarcoma as well as low-grade sarcoma but not for leiomyosarcoma or high-grade sarcoma. CONCLUSION: Thanks to international collaboration an academic randomized trial was even feasible in such a rare disease as RPS. The results of the STRASS study have relativized the potential benefit of radiotherapy in RPS. A longer follow-up especially regarding the role of radiotherapy in liposarcomas is desirable.

Distress in hospitalized cancer patients: Associations with personality traits, clinical and psychosocial characteristics.

OBJECTIVE: To improve allocation of psychosocial care and to provide patient-oriented support offers, identification of determinants of elevated distress is needed. So far, there is a lack of evidence investigating the interplay between individual disposition and current clinical and psychosocial determinants of distress in the inpatient setting. METHODS: In this cross-sectional study, we investigated 879 inpatients with different cancer sites treated in a German Comprehensive Cancer Center. Assessment of determinants of elevated distress included sociodemographic, clinical and psychosocial characteristics as well as dimensions of personality. Multiple linear regression was applied to identify determinants of psychosocial distress. RESULTS: Mean age of the patients was M = 61.9 (SD = 11.8), 48.1% were women. In the multiple linear regression model younger age (ß = -0.061, p = 0.033), higher neuroticism (ß = 0.178, p = <0.001), having metastases (ß = 0.091, p = 0.002), being in a worse physical condition (ß = 0.380, p = <0.001), depressive symptoms (ß = 0.270, p = <0.001), not feeling well informed about psychological support (ß = 0.054, p = 0.046) and previous uptake of psychological treatment (ß = 0.067, p = 0.020) showed significant associations with higher psychosocial distress. The adjusted R2 of the overall model was 0.464. CONCLUSION: Controlling for sociodemographic characteristics and dispositional vulnerability, that is neuroticism, current clinical and psychosocial characteristics were still associated with hospitalized patients' psychosocial distress. Psycho-oncologists should address both, the more transient emotional responses, such as depressive symptoms, as well as more enduring patient characteristics, like neuroticism.

Characterization of immune landscape in papillary thyroid cancer reveals distinct tumor immunogenicity and implications for immunotherapy.

Although the vast majority of patients with papillary thyroid cancer (PTC) have a favorable prognosis when conventional treatments are implemented, local recurrence and distant metastasis of advanced PTCs still hamper the survival and clinical management in certain patients. As immune checkpoint blockade (ICB) therapy achieves a great success in some advanced cancers, we aimed to investigate the immune landscape in PTC and its potential implications for prognosis and immunotherapy. In this study, different algorithms were conducted to estimate immune infiltration in PTC samples. A series of bioinformatic and machine learning approaches were performed to identify PTC-specific immune-related genes (IRGs) and distinct immune clusters. Differences in intrinsic tumor immunogenicity and potential immunotherapy response were observed between distinct immune clusters. A prognostic immune-related signature (IRS) was established to predict progression-free survival (PFS). IRS exhibited more powerful prognostic capacity and accurate survival prediction compared to conventional clinicopathological features. Furthermore, an integrated survival decision tree and a scoring nomogram were constructed to improve prognostic stratification and predictive accuracy for individual patients. In addition, altered pathways, mutational patterns, and potential applicable drugs were analyzed in different immune-related risk groups. Our study gained some insight into the immune landscape of PTC, and provided some useful clues for introducing immune-based molecular classification into risk stratification and guiding ICB decision-making.

Pembrolizumab-induced myocarditis in a patient with malignant mesothelioma: plasma exchange as a successful emerging therapy-case report.

Malignant mesothelioma is an aggressive cancer associated with prior exposure to asbestos and dismal prognosis. Immune checkpoint inhibitor therapy is currently approved by the Food and Drug Administration for pre-treated malignant pleural mesothelioma. We describe a 75-year-old patient with disseminated, progressive malignant mesothelioma receiving 2 cycles of pembrolizumab who presented with generalized muscle weakness, shortness of breath, double vision and ptosis. There was no previous history of cardiovascular disease. The clinical picture, supported by the detection of anti-titin autoantibodies suggested myasthenia gravis (MG). Also, cardiac biomarkers were elevated. Echocardiography showed new severely reduced ejection fraction. A 12-lead resting electrocardiogram (ECG) revealed ST segment elevation in the posterior leads with polymorphic ventricular extrasystoles. Because cardiac catheterization revealed no relevant coronary lesions, immune checkpoint inhibitor-associated myocarditis and MG were suspected. Management and Outcome: The patient was started on steroids. Within a few days of presentation respiratory failure set in and the patient was intubated. Recurrent arrhythmias followed, which were treated by repeated emergency electrical cardioversion. In order to relieve myasthenic symptoms, plasma exchange was initiated and 10 cycles were carried out. This consequently also led to an improvement of myocarditis. Upon discharge, the ejection fraction recovered. The patient recovered and was alive at 1-year follow-up, without relevant limitations to his quality of life. Discussion and Conclusion: The article further discusses the use of plasma exchange for immune checkpoint inhibitor-associated myocarditis based on a review of literature. We conclude that patients showing no improvement after steroid therapy for immune checkpoint inhibitor-related myocarditis should be evaluated for plasma exchange, which appears to be an effective treatment option.

Radiation to the Primary Tumor in Metastatic Anaplastic Thyroid Cancer.

BACKGROUND/AIM: Metastatic anaplastic thyroid cancer is associated with a dismal prognosis. We evaluated outcome and prognostic factors in patients receiving radiation to the primary tumor in metastatic anaplastic thyroid cancer (ATC). PATIENTS AND METHODS: All consecutive patients with metastatic ATC (n=20) undergoing irradiation between 2009 and 2019 for anaplastic thyroid cancer were investigated. RESULTS: Median survival time and median progression-free survival were 2 (range=1-22) and 2 (1-20) months. In univariate analyses, surgery, concurrent or sequential chemotherapy and higher radiation dose escalation (>39 Gy) were correlated with longer overall survival (p=0.005, p=0.018 and p=0.038), respectively. Karnofsky performance status >70% showed a trend of longer survival time (p=0.062). Limited metastatic disease, surgery and concurrent/sequential chemotherapy are correlated with longer progression-free survival times (p=0.043, p=0.024 and p=0.039), respectively. CONCLUSION: Radiation to the primary tumor in metastatic anaplastic thyroid cancer is safe and offers durable local control. Treatment intensification including concurrent or sequential chemotherapy and radiation dose escalation were associated with longer survival rates and should be considered in selected patients with metastatic disease.

Clinical Outcome and Toxicity in the Treatment of Anaplastic Thyroid Cancer in Elderly Patients.

BACKGROUND: The present study aims to evaluate the outcomes and toxicity of elderly anaplastic thyroid cancer (ATC) patients receiving (chemo)radiotherapy, as well as to identify prognostic factors. PATIENTS AND METHODS: A systematic review using the MEDLINE/PubMed and Cochrane databases was performed. Individual data from all eligible studies were extracted, and a pooled analysis (n = 186) was conducted to examine patient characteristics and treatment. All consecutive ATC patients (≥65 years) treated between 2009 and 2019 at our institution were evaluated for outcomes concerning progression-free survival (PFS), overall survival (OS) probabilities and treatment-related toxicity. RESULTS: The systematic review and pooled analysis identified age as a prognostic factor. The median OS of our patient cohort (n = 26) was three months (range = 0-125). The 6-, 12- and 24-month survival rates were 35%, 22% and 11%, respectively. In the univariate analysis, a Karnofsky performance status of >70%, the Union for International Cancer Control Tumor-Node-Metastasis classification, multimodal therapy and an EQD2 of >49 Gy were correlated with longer OS and PFS. The acute grade 3 toxicity of dysphagia, dyspnea, dermatitis, mucositis and dysphonia was found in 23%, 15%, 12%, 12% and 8% of patients. CONCLUSION: Age appears to be a prognostic factor in ATC. Elderly ATC patients can tolerate multimodal treatment and achieve a promising outcome. Prospective studies need to confirm our findings.

Hypofractionated Radiotherapy for Anaplastic Thyroid Cancer: Systematic Review and Pooled Analysis.

Anaplastic thyroid carcinoma (ATC) is associated with a poor prognosis due to aggressive tumor growth and high treatment resistance. Hypofractionated treatment concepts may be more effective and less time consuming compared to normofractionated radiotherapy (RT). In this retrospective study, we aim to evaluate the outcome of hypofractionated regimens and perform a systematic review concerning hypofractionated RT and pooled analysis of this treatment modality. A systematic review using the MEDLINE/Pubmed and Cochrane databases was performed. Data from all eligible studies were extracted, and a pooled analysis of literature and our cohort (n = 60) was carried out to examine patient characteristics, toxicity, and outcomes of patients with ATC. As a result, median overall survival (OS) of the single center cohort was four (range 1-12) months. Survival rates at one, three, and six months were 82%, 55%, and 36%, respectively. In univariate analyses, multimodal treatment (p = 0.006) and gender (p = 0.04) were correlated with an improved OS. Six studies with a total number of 152 patients undergoing hypofractionated RT treatment were analyzed. The pooled analysis included four patient cohorts with 60 patients and showed median OS of 5.3 (range: 1-24) months. Multimodal treatment (p < 0.001) and a cumulative radiation dose ≥50 Gy in equivalent dose in 2 Gy fractions (EQD2) (p = 0.014) correlated with an improved OS. On multivariate analysis, multimodal treatment (p = 0.003, hazard ratio (HR): 0.636, 95% confidence interval (CI): 0.469-0.861) was an independent predictor for longer OS. After propensity score matching (PSM), hypofractionated RT appears to be non-inferior compared to normofractionated RT concerning OS. In conclusion, hypofractionated RT is effective with manageable toxicity. A dose escalation with ≥50 Gy (EQD2) correlated with a longer OS. Hypofractionated RT could be an integral part in multimodal treatment with a promising outcome.

SARS-CoV-2 prevalence in an asymptomatic cancer cohort - results and consequences for clinical routine.

BACKGROUND: Starting in December 2019, the current pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) confronts the world with an unprecedented challenge. With no vaccine or drug being currently available to control the pandemic spread, prevention and PCR (Polymerase chain reaction) testing becomes a crucial pillar of medical systems. Aim of the present study was to report on the first results of the measures taken in a large German Department of Radiation Oncology, including PCR testing of asymptomatic cancer patients. METHODS: Pandemic-adapted hygiene regulations and prevention measures for patients and staff were implemented. A visiting ban on both wards was implemented from the beginning and medical staff and patients were required to wear face masks at all times. The waiting rooms were rearranged to ensure distance between patients of at least 1.5 m. Clinical follow up was mainly done by telephone and all patients had to complete a questionnaire regarding symptoms and contacts with COVID-19 patients before entering our department. Educational documents were created for patients to raise awareness of symptoms and avoidance strategies for interactions with other people. Indications for therapy and fractionation schemes were adapted when possible. In a subsequent step, all new asymptomatic patients were tested via nasopharyngeal swab at our screening station shortly before their simulation CT. RESULTS: All these measures and implementations have been well accepted semiquantitatively measured by the consent received from patients and staff. Regarding the PCR testing, only 1 out of 139 asymptomatic patients of our cohort so far tested positive for SARS-CoV-2, reflecting a prevalence of 0.72% in this cancer patient population. Up to this point no staff members was tested positive. The start of the treatment for the PCR-positive patient was deferred for 2 weeks. CONCLUSION: Due to the pandemic-adapted implementations, our department seems well prepared during this crisis. The initial screening helps to identify asymptomatic COVID-19 patients in order to protect other patients and our staff from infection and the observed PCR prevalence is in line with comparable studies. A regular PCR testing (e.g. twice a week) of all patients and staff would in principle be desirable but is limited due to testing capacities at present.

Factors associated with the decline of psychological support in hospitalized patients with cancer.

OBJECTIVE: Many distressed cancer patients do not want or, finally, do not use psychological support. This study aimed at identifying factors associated with the decline of psychological support during hospital stay. METHODS: This cross-sectional study included inpatients with different cancer diagnoses. Distress was assessed using the short form of the Questionnaire on Stress in Cancer Patients-Revised (QSC-R10) and the Distress Thermometer (DT). Multivariable logistic regression was used to identify factors associated with decline. RESULTS: Of 925 patients, 71.6% (n = 662) declined psychological support. Male sex (OR = 2.54, 95% CI = 1.69-3.80), low psychosocial distress (OR = 3.76, CI = 2.50-5.67), not feeling depressed (OR = 1.93, CI = 1.24-2.99), perceived overload (OR = 3.37, CI = 2.19-5.20), no previous psychological treatment (OR = 1.88, CI = 1.25-2.83), and feeling well informed about psychological support (OR = 1.66, CI = 1.11-2.46) were associated with decline. Among the patients who indicated clinical distress (46.2%), 53.9% declined psychological support. Male sex (OR = 2.96, CI = 1.71-5.12), not feeling depressed (OR = 1.87, CI = 1.12-3.14), perceived overload (OR = 5.37, CI = 3.07-9.37), agreeableness (OR = 0.70, CI = 0.51-0.95), and feeling well informed about psychological support (OR = 1.81, CI = 1.07-3.07) were uniquely associated with decline in this subgroup. CONCLUSIONS: Decline of psychological support is primarily due to psychological factors. Feeling well informed about support emerged as a relevant factor associated with decline. Thus, design of informational material and education about available psychological services seem crucial.

External-beam radiation therapy combined with limb-sparing surgery in elderly patients (>70 years) with primary soft tissue sarcomas of the extremities : A retrospective analysis.

PURPOSE: To report our experience with EBRT combined with limb-sparing surgery in elderly patients (>70 years) with primary extremity soft tissue sarcomas (STS). METHODS: Retrospectively analyzed were 35 patients (m:f 18:17, median 78 years) who all presented in primary situation without nodal/distant metastases (Charlson score 0/1 in 18 patients; ≥2 in 17 patients). Median tumor size was 10 cm, mainly located in lower limb (83%). Stage at presentation (UICC7th) was Ib:3%, 2a:20%, 2b:20%, and 3:57%. Most lesions were high grade (97%), predominantly leiomyosarcoma (26%) and undifferentiated pleomorphic/malignant fibrous histiocytoma (23%). Limb-sparing surgery was preceded (median 50 Gy) or followed (median 66 Gy) by EBRT. RESULTS: Median follow-up was 37 months (range 1-128 months). Margins were free in 26 patients (74%) and microscopically positive in 9 (26%). Actuarial 3­ and 5­year local control rates were 88 and 81% (4 local recurrences). Corresponding rates for distant control, disease-specific survival, and overall survival were 57/52%, 76/60%, and 72/41%. The 30-day mortality was 0%. Severe postoperative complications were scored in 8 patients (23%). Severe acute radiation-related toxicity was observed in 2 patients (6%). Patients with Charlson score ≥2 had a significantly increased risk for severe postoperative complications and acute radiation-related side effects. Severe late toxicities were found in 7 patients (20%), including fractures in 3 (8.6%). Final limb preservation rate was 97%. CONCLUSION: Combination of EBRT and limb-sparing surgery is feasible in elderly patients with acceptable toxicities and encouraging but slightly inferior outcome compared to younger patients. Comorbidity correlated with postoperative complications and acute toxicities. Late fracture risk seems slightly increased.

Excellent local control and survival after postoperative or definitive radiation therapy for sarcomas of the head and neck.

BACKGROUND: To report our results with postoperative or definitive radiation therapy in head and neck sarcomas. METHODS: We performed a retrospective analysis of 26 patients suffering from head and neck sarcomas, who received postoperative or definitive radiation therapy between 2003 and 2012. Median age was 64 years (19-88) and 69 % were male. Tumor locations were skull (including skin) in 31 %, paranasal sinus/orbita in 27 % and neck (including pharynx/larynx) in 42 %. Median tumor size was 4.6 cm (1-12 cm). 22 patients (85 %) presented in primary situation. Stage at presentation (UICC 7(th) for soft tissue sarcomas) was as follows: Ia:4 %, IIa:50 %, IIb:15 %, III:31 %. All except one patient suffered from high grade lesions (G2/3 FNCLCC), predominantly angiosarcoma (35 %), MFH (19 %) and synovial sarcoma (15 %). Surgery was performed in 21 pts (81 %), resulting in free margins in 10 (38 %), microscopically positive margins in 6 (23 %) and gross residual disease in 5 (19 %). Median dose to the primary tumor region was 66Gy (45-72Gy) in conventional fractionation, using 3D-CRT in 65 %, IMRT in 27 % and electrons in 8 %. 50 % of the patients also received sequential chemotherapy. RESULTS: Median follow up was 39 months (8-136). We observed three local recurrences, transferring into estimated 3- and 5-year local control rates of 86 %. One additional patient failed distantly, resulting in 3- and 5-year freedom from treatment failure rates of 82 %. Four patients have deceased, transferring into 3- and 5-year overall survival rates of 88 % and 82 %, respectively. Only two of the four deaths were sarcoma related. Maximum acute toxicity (CTCAE 3.0) was grade 1 in 27 % of the patients, grade 2 in 50 % and grade 3 in 23 %. Severe acute toxicity was mainly represented by mucositis and dysphagia. Maximum late toxicity was grade 1 in 31 %, grade 2 in 15 % and grade 3 in 19 % of the patients. Severe late toxicity included skin ulceration (n = 1), dysphagia with persistent tube dependency (n = 1), persistent sinusitis (n = 1) and hearing loss (n = 2). CONCLUSION: Excellent local control and overall survival rates can be achieved with postoperative or definitive radiation therapy with acceptable acute and late toxicities in patients suffering from sarcomas of the head and neck region.

PET response criteria in solid tumors predicts progression-free survival and time to local or distant progression after chemotherapy with regional hyperthermia for soft-tissue sarcoma.

UNLABELLED: We evaluated the prognostic accuracy of established PET and CT response criteria in patients with soft-tissue sarcoma (STS) after combined chemotherapy plus regional hyperthermia (RHT). METHODS: Seventy-three patients underwent (18)F-FDG PET/CT before and after 2-4 cycles of neoadjuvant chemotherapy with RHT for STS. Progression-free survival (PFS) and time to local and distant progression were among other factors correlated with response according to PET Response Criteria in Solid Tumors (PERCIST 1.0) and Response Evaluation Criteria in Solid Tumors (RECIST 1.1). RESULTS: Metabolic response by PERCIST (n = 44/73) was an independent predictor for PFS (P = 0.002; hazard ratio [HR], 0.35; 95% confidence interval [CI], 0.18-0.68) and time to local or distant progression. Other independent predictors for PFS by multivariate analysis were adjuvant radiotherapy (P = 0.010; HR, 0.39; 95% CI, 0.20-0.80) and a baseline tumor size less than 5.7 cm (P = 0.012; HR, 0.43; 95% CI, 0.22-0.83). Response by RECIST 1.1 was seen in a small group of patients (n = 22/73) and allowed prediction of PFS for patients with sarcoma outside the abdomen (P = 0.048; HR, 0.13; 95% CI, 0.02-0.98). CONCLUSION: Metabolic response by (18)F-FDG PET predicts PFS and time to local and distant progression after 2-4 cycles of neoadjuvant chemotherapy plus RHT for STS.

Tissue levels of reduced folates in patients with colorectal carcinoma after infusion of folinic acid at various dose levels.

PURPOSE: In patients with colorectal cancer (CRC), modulation of 5-fluorouracil (5-FU) by folinic acid (FA) improves response rate and overall survival compared with 5-FU alone. However, the optimal dose of FA is still debated. We investigated reduced folate pools in various tissues from patients with CRC without and after prior administration of FA. EXPERIMENTAL DESIGN: A total of 186 specimens (normal colorectal mucosa, primary colorectal tumor, normal liver, and liver metastases) from 86 consecutive patients with CRC were obtained and investigated for levels of reduced folates. Before surgery, patients did (n = 52) or did not (n = 34) receive FA as 15-minute i.v. infusion. FA-dose levels chosen were 20, 200, or 500 mg/m2. Tissue lysates were analyzed for reduced folate levels by means of the tritium release assay. RESULTS: In normal mucosa, combined pools of tetrahydrofolate and 5,10-methylenetetra-hydrofolate were significantly elevated at all FA dose levels compared with untreated controls. In primary tumor, only 200 and 500 mg/m2 FA resulted in a significant increase of reduced folates with highest values measured after 500 mg/m2 FA. In specimens from normal liver, folate levels did not increase after administration of FA. By contrast, in specimens from liver metastases, reduced folate levels were low without FA pretreatment compared with levels from normal liver samples. Infusion of 500 mg/m2 FA caused a significant increase of reduced folate levels in liver metastases. CONCLUSIONS: From a pharmacologic point of view, high-dose FA should be recommended for optimal modulation of 5-FU in patients with mCRC.