Combination of Lenvatinib and Pembrolizumab Is an Effective Treatment Option for Anaplastic and Poorly Differentiated Thyroid Carcinoma.

Background: Anaplastic thyroid carcinoma (ATC) and metastatic poorly differentiated thyroid carcinomas (PDTCs) are rare aggressive malignancies with poor overall survival (OS) despite extensive multimodal therapy. These tumors are highly proliferative, with frequently increased tumor mutational burden (TMB) compared with differentiated thyroid carcinomas, and elevated programmed death ligand 1 (PD-L1) levels. These tumor properties implicate responsiveness to antiangiogenic and antiproliferative multikinase inhibitors such as lenvatinib, and immune checkpoint inhibitors such as pembrolizumab. Patients and Methods: In a retrospective study, we analyzed six patients with metastatic ATC and two patients with PDTC, who received a combination therapy of lenvatinib and pembrolizumab. Lenvatinib was started at 14-24 mg daily and combined with pembrolizumab at a fixed dose of 200 mg every three weeks. Maximum treatment duration with this combination was 40 months, and 3 of 6 ATC patients are still on therapy. Patient tumors were characterized by whole-exome sequencing and PD-L1 expression levels (tumor proportion score [TPS] 1-90%). Results: Best overall response (BOR) within ATCs was 66% complete remissions (4/6 CR), 16% stable disease (1/6 SD), and 16% progressive disease (1/6 PD). BOR within PDTCs was partial remission (PR 2/2). The median progression-free survival was 17.75 months for all patients, and 16.5 months for ATCs, with treatment durations ranging from 1 to 40 months (1, 4, 11, 15, 19, 25, 27, and 40 months). Grade III/IV toxicities developed in 4 of 8 patients, requiring dose reduction/discontinuation of lenvatinib. The median OS was 18.5 months, with three ATC patients being still alive without relapse (40, 27, and 19 months) despite metastatic disease at the time of treatment initiation (UICC and stage IVC). All patients with long-term (>2 years) or complete responses (CRs) had either increased TMB or a PD-L1 TPS >50%. Conclusions: Our results implicate that the combination of lenvatinib and pembrolizumab might be safe and effective in patients with ATC/PDTC and can result in complete and long-term remissions. The combination treatment is now being systematically examined in a phase II clinical trial (Anaplastic Thyroid Carcinoma Lenvatinib Pembrolizumab [ATLEP]) in ATC/PDTC patients.

REQUITE: A prospective multicentre cohort study of patients undergoing radiotherapy for breast, lung or prostate cancer.

PURPOSE: REQUITE aimed to establish a resource for multi-national validation of models and biomarkers that predict risk of late toxicity following radiotherapy. The purpose of this article is to provide summary descriptive data. METHODS: An international, prospective cohort study recruited cancer patients in 26 hospitals in eight countries between April 2014 and March 2017. Target recruitment was 5300 patients. Eligible patients had breast, prostate or lung cancer and planned potentially curable radiotherapy. Radiotherapy was prescribed according to local regimens, but centres used standardised data collection forms. Pre-treatment blood samples were collected. Patients were followed for a minimum of 12 (lung) or 24 (breast/prostate) months and summary descriptive statistics were generated. RESULTS: The study recruited 2069 breast (99% of target), 1808 prostate (86%) and 561 lung (51%) cancer patients. The centralised, accessible database includes: physician- (47,025 forms) and patient- (54,901) reported outcomes; 11,563 breast photos; 17,107 DICOMs and 12,684 DVHs. Imputed genotype data are available for 4223 patients with European ancestry (1948 breast, 1728 prostate, 547 lung). Radiation-induced lymphocyte apoptosis (RILA) assay data are available for 1319 patients. DNA (n = 4409) and PAXgene tubes (n = 3039) are stored in the centralised biobank. Example prevalences of 2-year (1-year for lung) grade ≥2 CTCAE toxicities are 13% atrophy (breast), 3% rectal bleeding (prostate) and 27% dyspnoea (lung). CONCLUSION: The comprehensive centralised database and linked biobank is a valuable resource for the radiotherapy community for validating predictive models and biomarkers. PATIENT SUMMARY: Up to half of cancer patients undergo radiation therapy and irradiation of surrounding healthy tissue is unavoidable. Damage to healthy tissue can affect short- and long-term quality-of-life. Not all patients are equally sensitive to radiation "damage" but it is not possible at the moment to identify those who are. REQUITE was established with the aim of trying to understand more about how we could predict radiation sensitivity. The purpose of this paper is to provide an overview and summary of the data and material available. In the REQUITE study 4400 breast, prostate and lung cancer patients filled out questionnaires and donated blood. A large amount of data was collected in the same way. With all these data and samples a database and biobank were created that showed it is possible to collect this kind of information in a standardised way across countries. In the future, our database and linked biobank will be a resource for research and validation of clinical predictors and models of radiation sensitivity. REQUITE will also enable a better understanding of how many people suffer with radiotherapy toxicity.

Long-term results after intraoperative radiation therapy for gastric cancer.

PURPOSE: We retrospectively analyzed the impact of intraoperative radiation therapy (IORT) on long-term survival in patients with resectable gastric cancer. METHODS AND MATERIALS: From 1991 to 2001, a total of 84 patients with gastric neoplasms underwent gastectomy or subtotal resection with IORT (23 Gy, 6-15 MeV; IORT-positive [IORT(+)] group). Patients with a history of additional neoadjuvant chemotherapy, histologically confirmed R1 or R2 resection, or reoperation with curative intention after local recurrence were excluded from further analysis. The remaining 61 patients were retrospectively matched with 61 patients without IORT (IORT-negative [IORT(-)] group) for Union Internationale Contre le Cancer (UICC) stage, patient age, histologic grading, extent of surgery, and level of lymph node dissection. Subgroups included postoperative UICC Stages I (n = 31), II (n = 11), III (n = 14), and IV (n = 5). RESULTS: Mean follow-up was 4.8 years in the IORT(+) group and 5.0 years in the IORT(-) group. The overall 5-year patient survival rate was 58% in the IORT(+) group vs. 59% in the IORT(-) group (p = 0.99). Subgroup analysis showed no impact of IORT on 5-year patient survival for those with UICC Stages I/II (76% vs. 80%; p = 0.87) and III/IV (21% vs. 14%, IORT(+) vs. IORT(-) group; p = 0.30). Perioperative mortality rates were 4.9% and 4.9% in the IORT(+) vs. IORT(-) group. Total surgical complications were more common in the IORT(+) than IORT(-) group (44.3% vs. 19.7%; p < 0.05). The locoregional tumor recurrence rate was 9.8% in the IORT(+) group. CONCLUSIONS: Use of IORT was associated with low locoregional tumor recurrence, but had no benefit on long-term survival while significantly increasing surgical morbidity in patients with curable gastric cancer.

Anemia and long-term outcome in adjuvant and neoadjuvant radiochemotherapy of stage II and III rectal adenocarcinoma: the Freiburg experience (1989-2002).

AIM: To evaluate the long-term outcome of standard 5-FU based adjuvant or neoadjuvant radiochemotherapy and to identify the predictive factors, especially anemia before and after radiotherapy as well as hemoglobin increase or decrease during radiotherapy. METHODS: Two hundred and eighty-six patients with Union International Contre Cancer (UICC) stage II and III rectal adenocarcinomas, who underwent resection by conventional surgical techniques (low anterior or abdominoperineal resection), received either postoperative (n=233) or preoperative (n=53) radiochemotherapy from January 1989 until July 2002. Overall survival (OAS), cancer-specific survival (CSS), disease-free survival (DFS), local-relapse-free (LRS) and distant-relapse-free survival (DRS) were evaluated using Kaplan-Meier, Log-rank test and Cox's proportional hazards as statistical methods. Multivariate analysis was used to identify prognostic factors. Median follow-up time was 8 years. RESULTS: Anemia before radiochemotherapy was an independent prognostic factor for improved DFS (risk ratio 0.76, P=0.04) as well as stage, grading, R status (free radial margins), type of surgery, carcinoembryonic antigen (CEA) levels, and gender. The univariate analysis revealed that anemia was associated with impaired LRS (better local control) but with improved DFS. In contrast, hemoglobin decrease during radiotherapy was an independent risk factor for DFS (risk ratio 1.97, P=0.04). During radiotherapy, only 30.8% of R0-resected patients suffered from hemoglobin decrease compared to 55.6% if R1/2 resection was performed (P=0.04). The 5-year OAS, CSS, DFS, LRS and DRS were 47.0%, 60.0%, 41.4%, 67.2%, and 84.3%, respectively. Significant differences between preoperative and postoperative radiochemotherapy were not found. CONCLUSION: Anemia before radiochemotherapy and hemoglobin decrease during radiotherapy have no predictive value for the outcome of rectal cancer. Stage, grading, R status (free radial margins), type of surgery, CEA levels, and gender have predictive value for the outcome of rectal cancer.

The proteasome inhibitor MG-132 sensitizes PC-3 prostate cancer cells to ionizing radiation by a DNA-PK-independent mechanism.

BACKGROUND: By modulating the expression levels of specific signal transduction molecules, the 26S proteasome plays a central role in determining cell cycle progression or arrest and cell survival or death in response to stress stimuli, including ionizing radiation. Inhibition of proteasome function by specific drugs results in cell cycle arrest, apoptosis and radiosensitization of many cancer cell lines. This study investigates whether there is also a concomitant increase in cellular radiosensitivity if proteasome inhibition occurs only transiently before radiation. Further, since proteasome inhibition has been shown to activate caspase-3, which is involved in apoptosis, and caspase-3 can cleave DNA-PKcs, which is involved in DNA-double strand repair, the hypothesis was tested that caspase-3 activation was essential for both apoptosis and radiosensitization following proteasome inhibition. METHODS: Prostate carcinoma PC-3 cells were treated with the reversible proteasome inhibitor MG-132. Cell cycle distribution, apoptosis, caspase-3 activity, DNA-PKcs protein levels and DNA-PK activity were monitored. Radiosensitivity was assessed using a clonogenic assay. RESULTS: Inhibition of proteasome function caused cell cycle arrest and apoptosis but this did not involve early activation of caspase-3. Short-time inhibition of proteasome function also caused radiosensitization but this did not involve a decrease in DNA-PKcs protein levels or DNA-PK activity. CONCLUSION: We conclude that caspase-dependent cleavage of DNA-PKcs during apoptosis does not contribute to the radiosensitizing effects of MG-132.

Adjuvant radiochemotherapy of stage II and III rectal adenocarcinoma: role of CEA and CA 19-9.

BACKGROUND: This analysis was undertaken to evaluate the impact of pre-radiotherapy CEA and CA 19-9 values on clinical outcome of locally advanced rectal cancer. PATIENTS AND METHODS: Retrospective data were collected from patients (n=203) with UICC stage II and III rectal adenocarcinomas, who underwent low anterior or abdominoperineal resection and received post-operative or pre-operative radiochemotherapy from January 1989 until July 2002. The rates of survival and distant and local recurrences were evaluated using Kaplan-Meier survival analysis, Log-rank test and Cox's proportional hazards (median follow-up 8 years). Multivariate analysis was used to assess the prognostic value of CEA and CA 19-9. RESULTS: The 5-year actuarial rates for patients with normal (n =118) and elevated (n=88) CEA values were as follows: overall survival 62.4% and 32.0% (p<0.001), local control 73.5% and 55.0% (p=0.007), and absence of distant metastasis 83.3% and 88.0% (n.s.), respectively. Similar results were obtained for patients with normal (n=82) and elevated (n = 10) CA 19-9 values: overall survival 60.7% and 14.0% (p=0.007), local control 83.7% and 80.0% (n.s.), and absence of distant metastasis 64.9% and 75.0% (n.s.), respectively. After adjustment for TNM stage, sex, age, LDH, tumor site and grading, the elevation of CEA proved to be an independent prognostic factor for overall survival (relative risk of 1.01 per ng/ml, CI 1.002 - 1.01; p=0.005). CONCLUSION: This study confirmed the prognostic value of pre-radiotherapy CEA and CA 19-9 in patients with stage II or III rectal carcinoma.

Patients with brain metastases from gastrointestinal tract cancer treated with whole brain radiation therapy: prognostic factors and survival.

AIM: To identify the prognostic factors with regard to survival for patients with brain metastasis from primary tumors of the gastrointestinal tract. METHODS: Nine hundred and sixteen patients with brain metastases, treated with whole brain radiation therapy (WBRT) between January 1985 and December 2000 at the Department of Radiation Oncology, University Hospital Freiburg, were analyzed retrospectively. RESULTS: Fifty-seven patients presented with a primary tumor of the gastrointestinal tract (esophagus: n = 0, stomach: n = 10, colorectal: n = 47). Twenty-six patients had a solitary brain metastasis, 31 patients presented with multiple brain metastases. Surgical resection was performed in 25 patients. WBRT was applied with daily fractions of 2 Gray (Gy) or 3 Gy to a total dose of 50 Gy or 30 Gy, respectively. The interval between diagnoses of the primary tumors and brain metastases was 22.6 mo vs 8.0 mo for patients with primary tumors of the colon/rectum vs other primary tumors, respectively (P<0.01, log-rank). Median overall survival for all patients with brain metastases (n = 916) was 3.4 mo and 3.2 mo for patients with gastrointestinal neoplasms. Patients with gastrointestinal primary tumors presented significantly more often with a solitary brain metastasis than patients with other primary tumors (P<0.05, log-rank). In patients with gastrointestinal neoplasms (n = 57), the median overall survival was 5.8 mo for patients with solitary brain metastasis vs 2.7 mo for patients with multiple brain metastases (P<0.01, log-rank). The median overall survival for patients with a Karnofsky performance status (KPS) >=70 was 5.5 mo vs 2.1 mo for patients with KPS <70 (P<0.01, log-rank). At multivariate analysis (Cox Model) the performance status and the number of brain metastases were identified as independent prognostic factors for overall survival. CONCLUSION: Brain metastases occur late in the course of gastrointestinal tumors. Pretherapeutic variables like KPS and the number of brain metastases have a profound influence on treatment outcome.

Do erythropoietin receptors on cancer cells explain unexpected clinical findings?

PURPOSE: Recent reports suggest that cancer control may worsen if erythropoietin is administered. We investigated whether erythropoietin receptor expression on cancer cells may correlate with this unexpected finding. PATIENTS AND METHODS: Cancer tissue from patients with advanced carcinoma of the head and neck (T3, T4, or nodal involvement) and scheduled for radiotherapy was assayed retrospectively for erythropoietin receptor expression by immunohistochemistry. Patients were anemic and randomized to receive epoetin beta (300 U/kg) or placebo under double-blind conditions, given three times weekly starting 10 to 14 days before and continuing throughout radiotherapy. We administered 60 Gy following complete resection or 64 Gy subsequent to microscopically incomplete resection; 70 Gy were given following macroscopically incomplete resection or for definitive radiotherapy alone. We determined if the effect of epoetin beta on locoregional progression-free survival was correlated with the expression of erythropoietin receptors on cancer cells using a Cox proportional hazards regression model. RESULTS: We studied 154 of 157 randomly assigned patients; 104 samples were positive, and 50 were negative for receptor expression. Locoregional progression-free survival was substantially poorer if epoetin beta was administered to patients positive for receptor expression compared with placebo (adjusted relative risk, 2.07; 95% CI, 1.27 to 3.36; P < .01). In contrast, epoetin beta did not impair outcome in receptor-negative patients (adjusted relative risk, 0.94; 95% CI, 0.47 to 1.90; P = .86). The difference in treatment associated relative risks (2.07 v 0.94) was borderline statistically significant (P = .08). CONCLUSION: Erythropoietin might adversely affect prognosis of head and neck cancer patients if cancer cells express erythropoietin receptors.

Gastrointestinal cancer web sites: how do they address patients' concerns?

BACKGROUND: We studied the quality of web sites containing information on gastrointestinal cancer, focusing on the way these web sites dealt with the special concerns of these patients. MATERIALS AND METHODS: Searching the Internet for German-language gastroenterological cancer web sites, we collected 9,947 web pages from 14 search engines. Evaluation was done with a 36-item questionnaire. Information quality, availability of the web sites, and web site attributes considering patients' concerns and potential embarrassment were analyzed using a scoring system. RESULTS: Belonging to 165 web sites, 1,763 of 9,947 (17.7%) web pages found by search engines provided relevant information. Five hundred forty-seven (5.5%) hits were partly relevant, and 7,637 (76.8%) were irrelevant or not available. Most web sites reported about surgery (92.1%), chemotherapy (88.5%), and radiotherapy (73.9%). Of the web sites, 46.7% (n=77), 34.6% (n=57), and 21.8% (n=36) gave information about the author(s) itself, their qualifications, and references of their information, respectively. Search engines ranked web sites giving no information on evidence-based medicine higher than other web sites, whereas web sites providing this information accurately showed higher link popularities. Patients' concerns and potential embarrassment were best addressed by gastrointestinal web sites initiated by private individuals or web sites directed to both a patient and physician audience. CONCLUSIONS: With regard to gastrointestinal cancer web sites, many search engines may be ineffective, and patient emotional needs and concerns are often disregarded. Also, physicians should guide their patients through the Internet to find high-quality information and use link-popularity-based search strategies.

Dominant role of prostaglandin E2 EP4 receptor in furosemide-induced salt-losing tubulopathy: a model for hyperprostaglandin E syndrome/antenatal Bartter syndrome.

Increased formation of prostaglandin E2 (PGE2) is a key part of hyperprostaglandin E syndrome/antenatal Bartter syndrome (HPS/aBS), a renal disease characterized by NaCl wasting, water loss, and hyperreninism. Inhibition of PGE2 formation by cyclo-oxygenase inhibitors significantly lowers patient mortality and morbidity. However, the pathogenic role of PGE2 in HPS/aBS awaits clarification. Chronic blockade of the Na-K-2Cl co-transporter NKCC2 by diuretics causes symptoms similar to HPS/aBS and provides a useful animal model. In wild-type (WT) mice and in mice lacking distinct PGE2 receptors (EP1-/-, EP2-/-, EP3-/-, and EP4-/-), the effect of chronic furosemide administration (7 d) on urine output, sodium and potassium excretion, and renin secretion was determined. Furthermore, furosemide-induced diuresis and renin activity were analyzed in mice with defective PGI2 receptors (IP-/-). In all animals studied, furosemide stimulated a rise in diuresis and electrolyte excretion. However, this effect was blunted in EP1-/-, EP3-/-, and EP4-/- mice. Compared with WT mice, no difference was observed in EP2-/- and IP-/- mice. The furosemide-induced increase in plasma renin concentration was significantly decreased in EP4-/- mice and to a lesser degree also in IP-/- mice. Pharmacologic inhibition of EP4 receptors in furosemide-treated WT mice with the specific antagonist ONO-AE3-208 mimicked the changes in renin mRNA expression, plasma renin concentration, diuresis, and sodium excretion seen in EP4-/- mice. The GFR in EP4-/- mice was not changed compared with that in WT mice, which indicated that blunted diuresis and salt loss seen in EP4-/- mice were not a consequence of lower GFR. In summary, these findings demonstrate that the EP4 receptor mediates PGE2-induced renin secretion and that EP1, EP3, and EP4 receptors all contribute to enhanced PGE2-mediated salt and water excretion in the HPS/aBS model.

Vitiligo at the sites of irradiation in a patient with Hodgkin's disease.

BACKGROUND: Vitiligo is one of the most common skin disorders. However, the etiology of vitiligo is still unknown. Current hypotheses discuss autoimmune, autotoxic and neuronal mechanisms. Here we report the case of radiation-induced depigmentation of the skin of a patient with Hodgkin's disease and 25-year history of vitiligo. PATIENT AND METHOD: We compared possible differences in skin color, skin moisture, microcirculation and skin elasticity between normal skin and skin exhibiting persistent depigmentation in a 37-year-old patient 40 months after completion of external beam radiotherapy. RESULTS: Colormetrically we found a dose-dependent decrease of the red/green and yellow/blue saturation combined with an overall increase in brightness in depigmented skin when compared with normal skin. This was in agreement with a loss of melanocytes in vitiligo. Depigmentation was complete in areas receiving 40 Gy. Areas which received 30 Gy showed depigmentation only if the skin dose was increased by the loss of depth of the build-up dose region in areas with direct contact with the irradiation table. We could not show any change in skin moisture, microcirculation or skin elasticity. CONCLUSIONS: Complete radiation-induced depigmentation of skin from patients suffering from vitiligo is a side effect of radiation therapy. Patients should be informed about this side effect by the radiooncologist. Preventing the loss of depth of the build-up dose region might improve the cosmetic results of radiation therapy in patients with history of vitiligo.

[On past practices and future directions of informed consent in (radiation) oncology]. / Qui nescit simulare nescit curare--Wer nicht täuschen kann, kann nicht heilen. Anmerkungen zur Aufklärung von Patienten in der (Radio-)Onkologie.

BACKGROUND AND PURPOSE: Informed consent, especially in oncology, is predominantly seen from a legal point of view. Such a limited perspective runs the risk of reducing informed consent to some tiresome formalism. The present article highlights how the relationship between patient and physician might be enriched by a comprehensive historicocultural understanding of informed consent. The authors show in which future directions the practice of informed consent might develop. MATERIAL AND METHODS: Analysis of historical and forensic literature regarding informed consent. RESULTS: With the terms "information" and "consent" the last 2500 years of medical history can schematically be divided in three epochs: the first epoch started around 500 years BC, lasted until the 19th century AC and was dominated by the principle of "salus aegroti suprema lex". The patient's benefit was exclusively defined by the treating physician. Formal consent was not required in those times. The era of enlightment brought new ideas to Europe, especially the principle of individual autonomy. In 1894, the Supreme Court of the German Reich decided that any medical intervention without the patient's consent was regarded as physical injury and was thus illegal. Systematic requirements regarding patient information on planned medical interventions were not known. The beginning of the third epoch is marked by the introduction of the term "informed consent" in modern medicine in 1957. Since then, a comprehensive information of the patient is seen as a prerequisite for consent. The patient's right of self-determination is attributed a higher legal and moral value than the physician's concept of the proposed treatment. Nowadays, the debate regarding informed consent is dominated by the continuing differentiation of modern medicine, the development of medical practice as part of the service sector, and the changing ways how patients see themselves. CONCLUSIONS: Social and legal developments have strongly influenced medical practice in the past. The importance of informed consent will continue to rise in the future, while the emphasis of the physician's task will shift from information to counseling. Informed consent will be increasingly established as independent service.

Moist skin care can diminish acute radiation-induced skin toxicity.

BACKGROUND: Radiation treatment may induce acute skin reactions. There are several methods of managing them. Validity of these methods, however, is not sufficiently studied. We therefore investigated, whether moist skin care with 3% urea lotion will reduce acute radiation skin toxicity. PATIENTS AND METHODS: 88 patients with carcinomas of the head and neck undergoing radiotherapy with curative intent (mean total dose 60 Gy, range: 50-74 Gy) were evaluated weekly for acute skin reactions according to the RTOG-CTC score. In 63 patients, moist skin care with 3% urea lotion was performed. The control group consisted of 25 patients receiving conventional dry skin care. The incidence of grade I, II, and III reactions and the radiation dose at occurrence of a particular reaction were determined and statistically analyzed using the log-rank test. The dose-time relations of individual skin reactions are described. RESULTS: At some point of time during radiotherapy, all patients suffered from acute skin reactions grade I, > 90% from grade II reactions. 50% of patients receiving moist skin care experienced grade I reactions at 26 Gy as compared to 22 Gy in control patients (p = 0.03). Grade II reactions occurred at 51 Gy versus 34 Gy (p = 0.006). Further, 22% of the patients treated with moist skin care suffered from acute skin toxicity grade III as compared to 56% of the controls (p = 0.0007). CONCLUSION: Moist skin care with 3% urea lotion delays the occurrence and reduces the grade of acute skin reactions in percutaneously irradiated patients with head and neck tumors.