RESUMO
BACKGROUND: Subsequent primary neoplasms (SPN) are among the most severe late effects and the second most frequent cause of death in childhood cancer patients. In this paper we introduce method and properties of the STATT-SCAR study (Second Tumor After Tumor Therapy, Second Cancer After Radiotherapy), which is a joint nested matched case-control study to evaluate the impact of chemotherapy (STATT) as well as radiotherapy (SCAR) on the risk of developing a SPN. METHODS: Based on the cohort of the German childhood cancer registry (GCCR), we selected patients diagnosed with a first neoplasm before age 15 or younger between 1980 and 2014. We selected those with a SPN at least half a year after the first neoplasm, and matched up to four controls to each case. Therapy data were acquired from various sources, including clinical study centers and treating hospitals. To analyze the impact of radiotherapy, organ doses were estimated by using reconstructed treatment plans. The effect of chemotherapy was analyzed using substance groups summarized after isotoxic dose conversion. RESULTS: 1244 cases with a SPN were identified and matched with 4976 controls. Treatment data were acquired for 83% of all match groups (one case and at least one control). Based on preliminary analyses, 98% of all patients received chemotherapy and 54% of all patients were treated with radiotherapy. CONCLUSIONS: Based on our data, detailed analyses of dose response relationships and treatment element combinations are possible, leading to a deeper insight into SPN risks after cancer treatments. TRIAL REGISTRATION: The study is registered at the German clinical trial register (DRKS) under number DRKS00017847 [45].
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Segunda Neoplasia Primária , Neoplasias , Criança , Humanos , Adolescente , Neoplasias/tratamento farmacológico , Neoplasias/epidemiologia , Neoplasias/radioterapia , Estudos de Casos e Controles , Segunda Neoplasia Primária/epidemiologia , Segunda Neoplasia Primária/etiologiaRESUMO
PURPOSE: Multiple myeloma is associated with osteolytic bone lesions, often requiring surgery of the spine and postoperative radiotherapy (RT). Although common, data for clinical and informed decision-making are sparse. In this monocentric retrospective study, we aim to report the outcome of patients who underwent spinal surgery and postoperative RT due to multiple myeloma. METHODS: A total of 54 patients with multiple myeloma who underwent prior spinal surgery and postoperative RT at our institution between 2009 and 2020 were analyzed. Spinal instability neoplastic score (SINS) and Bilsky score, posttherapeutic adverse events, clinical data, and outcomes were collected and analyzed. The primary endpoint of this study was overall survival (OS), secondary endpoints were progression-free survival (PFS), pain response, local control, and skeletal-related events (SRE). RESULTS: The 3 and 5year overall survival (OS) was 74.9% (95% confidence interval [CI]: 63.5-88.4%) and 58% (95% CI: 44.5-75.6%), respectively. Median survival was not reached and 75% survival was 34.3 months (95% CI: 28.7-95.4 months). Median follow-up was 63 months (95% CI: 49-94 months). The number of patients with good to adequate performance status (Karnofsky performance score [KPS] ≥â¯70) significantly increased after surgery (pâ¯< 0.01). We observed no grade 3/4 toxicity and only 13 (24%) grade 1/2 adverse events. Two patients (4%) experienced SRE. Overall, 92% of patients reported reduced pain after radiotherapy, with 66% reporting complete pain response. There was no difference in pain response between patients with different Bilsky scores. Bisphosphonate therapy and lower Bilsky score at the start of RT were associated with improved OS in univariate analysis (all pâ¯< 0.05). Multivariate Cox regression confirmed a Bilsky score of 2 or 3 as an independent negative prognostic factor (HR 3.89; 95 CI 1.4-10.7; pâ¯< 0.01). We observed no in-field recurrences. CONCLUSION: In this study, we were able to show that the current standard of RT after spinal surgery of osteolytic lesions is safe. In addition, we observed a very low rate of SRE (4%) and no in-field recurrences, demonstrating the local efficacy of RT in multiple myeloma patients. Higher Bilsky scores were associated with worse OS in multivariate analysis, but had no effect on pain response.
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Mieloma Múltiplo , Humanos , Mieloma Múltiplo/radioterapia , Mieloma Múltiplo/mortalidade , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Estudos Retrospectivos , Neoplasias da Coluna Vertebral/radioterapia , Neoplasias da Coluna Vertebral/cirurgia , Neoplasias da Coluna Vertebral/mortalidade , Idoso de 80 Anos ou mais , Radioterapia Adjuvante , Intervalo Livre de Progressão , Adulto , Resultado do Tratamento , Dor do Câncer/radioterapia , Dor do Câncer/etiologiaRESUMO
BACKGROUND: Differential expression analysis is usually adjusted for variation. However, most studies that examined the expression variability (EV) have used computations affected by low expression levels and did not examine healthy tissue. This study aims to calculate and characterize an unbiased EV in primary fibroblasts of childhood cancer survivors and cancer-free controls (N0) in response to ionizing radiation. METHODS: Human skin fibroblasts of 52 donors with a first primary neoplasm in childhood (N1), 52 donors with at least one second primary neoplasm (N2 +), as well as 52 N0 were obtained from the KiKme case-control study and exposed to a high (2 Gray) and a low dose (0.05 Gray) of X-rays and sham- irradiation (0 Gray). Genes were then classified as hypo-, non-, or hyper-variable per donor group and radiation treatment, and then examined for over-represented functional signatures. RESULTS: We found 22 genes with considerable EV differences between donor groups, of which 11 genes were associated with response to ionizing radiation, stress, and DNA repair. The largest number of genes exclusive to one donor group and variability classification combination were all detected in N0: hypo-variable genes after 0 Gray (n = 49), 0.05 Gray (n = 41), and 2 Gray (n = 38), as well as hyper-variable genes after any dose (n = 43). While after 2 Gray positive regulation of cell cycle was hypo-variable in N0, (regulation of) fibroblast proliferation was over-represented in hyper-variable genes of N1 and N2+. In N2+, 30 genes were uniquely classified as hyper-variable after the low dose and were associated with the ERK1/ERK2 cascade. For N1, no exclusive gene sets with functions related to the radiation response were detected in our data. CONCLUSION: N2+ showed high degrees of variability in pathways for the cell fate decision after genotoxic insults that may lead to the transfer and multiplication of DNA-damage via proliferation, where apoptosis and removal of the damaged genome would have been appropriate. Such a deficiency could potentially lead to a higher vulnerability towards side effects of exposure to high doses of ionizing radiation, but following low-dose applications employed in diagnostics, as well.
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Sobreviventes de Câncer , Neoplasias , Humanos , Criança , Perfilação da Expressão Gênica , Neoplasias/genética , Neoplasias/radioterapia , Estudos de Casos e Controles , Radiação Ionizante , Expressão Gênica , Relação Dose-Resposta à RadiaçãoRESUMO
PURPOSE: Diffuse large Bcell lymphoma (DLBCL) is an aggressive lymphoma subtype treated successfully with immunochemotherapy. However, there are conflicting data on the role and impact of consolidative radiation therapy (RT). The publication of the national evidence-based guideline on DLBCL prompted us to review relevant passages on radiation oncology. METHODS: The following article reviews the evidence and recommendations given in the current German evidence-based guideline on DLBCL regarding RT and summarizes pivotal aspects. Additional literature is presented to provide a comprehensive background for the published recommendations. RESULTS: RT shall be administered to all patients with localized positron emission tomography(PET)-positive residues after completion of immunochemotherapy and should use a dose of 30-40â¯Gray in normofractionation. For RT planning, PET information before and after immunochemotherapy shall be used, with either a PET-CT in the RT treatment position or an image fusion to the planning CT. Conformal techniques shall be used for target volume coverage, with a risk-benefit evaluation for the individual patient. Additionally, RT may be used in the treatment context of various subtypes of DLBCL as well as in the recurrent or refractory treatment situation. CONCLUSION: RT remains an integral part of the treatment repertoire of DLBCL. With the use of PET-guided treatment, RT is indicated for patients with metabolically active tumors. In the context of the ongoing development of targeted therapies, new RT indications may evolve.
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Linfoma Difuso de Grandes Células B , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Humanos , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Radio-Oncologistas , Linfoma Difuso de Grandes Células B/diagnóstico por imagem , Linfoma Difuso de Grandes Células B/radioterapia , Tomografia por Emissão de PósitronsRESUMO
Locally advanced head and neck squamous cell carcinomas (HNSCC) are often refractory to platinum-based radiochemotherapy and new immuno-oncological strategies. To stimulate immunogenic antitumor responses in HNSCC patients, we investigated the cGAS/STING/IFN-1 signaling pathway after genotoxic treatments and concomitant abrogation of the DNA damage response (DDR). For this purpose, FaDu and UM-SCC1 cells were exposed to X-rays or cisplatin and treated with an ATR or Chk1 inhibitor, or by Fanconi anemia gene A knockout (FANCA ko). We assessed clonogenic survival, cell cycle regulation, micronuclei, free cytosolic double-stranded DNA, and the protein expression and activity of the cGAS/STING/IFN-1 pathway and related players. Cell survival, regulation of G2/M arrest, and formation of rupture-prone cGAS-positive micronuclei after genotoxic treatments were most affected by ATR inhibition and FANCA ko. In UM-SCC-1 cells only, 8 Gy X-rays promoted IFN-1 expression unaltered by abrogation of the DDR or concomitant increased TREX1 expression. At a higher dose of 20 Gy, this effect was observed only for concurrent Chk1- or ATR-inhibition. FANCA ko or cisplatin treatment was ineffective in this regard. Our observations open new perspectives for the enhancement of cGAS/STING/IFN-1-mediated antitumor immune response in HNSCC by hypofractionated or stereotactic radiotherapy concepts in multimodal settings with immuno-oncological strategies.
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Anemia de Fanconi , Neoplasias de Cabeça e Pescoço , Humanos , Carcinoma de Células Escamosas de Cabeça e Pescoço/genética , Cisplatino/farmacologia , Cisplatino/metabolismo , Apoptose , Linhagem Celular Tumoral , Pontos de Checagem da Fase G2 do Ciclo Celular , Neoplasias de Cabeça e Pescoço/genética , Dano ao DNA , Nucleotidiltransferases/genética , Nucleotidiltransferases/metabolismo , Proteínas Mutadas de Ataxia Telangiectasia/genética , Proteínas Mutadas de Ataxia Telangiectasia/metabolismoRESUMO
BACKGROUND: The etiology and most risk factors for a sporadic first primary neoplasm in childhood or subsequent second primary neoplasms are still unknown. One established causal factor for therapy-associated second primary neoplasms is the exposure to ionizing radiation during radiation therapy as a mainstay of cancer treatment. Second primary neoplasms occur in 8% of all cancer survivors within 30 years after the first diagnosis in Germany, but the underlying factors for intrinsic susceptibilities have not yet been clarified. Thus, the purpose of this nested case-control study was the investigation and comparison of gene expression and affected pathways in primary fibroblasts of childhood cancer survivors with a first primary neoplasm only or with at least one subsequent second primary neoplasm, and controls without neoplasms after exposure to a low and a high dose of ionizing radiation. METHODS: Primary fibroblasts were obtained from skin biopsies from 52 adult donors with a first primary neoplasm in childhood (N1), 52 with at least one additional primary neoplasm (N2+), as well as 52 without cancer (N0) from the KiKme study. Cultured fibroblasts were exposed to a high [2 Gray (Gy)] and a low dose (0.05 Gy) of X-rays. Messenger ribonucleic acid was extracted 4 h after exposure and Illumina-sequenced. Differentially expressed genes (DEGs) were computed using limma for R, selected at a false discovery rate level of 0.05, and further analyzed for pathway enrichment (right-tailed Fisher's Exact Test) and (in-) activation (z ≥|2|) using Ingenuity Pathway Analysis. RESULTS: After 0.05 Gy, least DEGs were found in N0 (n = 236), compared to N1 (n = 653) and N2+ (n = 694). The top DEGs with regard to the adjusted p-value were upregulated in fibroblasts across all donor groups (SESN1, MDM2, CDKN1A, TIGAR, BTG2, BLOC1S2, PPM1D, PHLDB3, FBXO22, AEN, TRIAP1, and POLH). Here, we observed activation of p53 Signaling in N0 and to a lesser extent in N1, but not in N2+. Only in N0, DNA (excision-) repair (involved genes: CDKN1A, PPM1D, and DDB2) was predicted to be a downstream function, while molecular networks in N2+ were associated with cancer, as well as injury and abnormalities (among others, downregulation of MSH6, CCNE2, and CHUK). After 2 Gy, the number of DEGs was similar in fibroblasts of all donor groups and genes with the highest absolute log2 fold-change were upregulated throughout (CDKN1A, TIGAR, HSPA4L, MDM2, BLOC1SD2, PPM1D, SESN1, BTG2, FBXO22, PCNA, and TRIAP1). Here, the p53 Signaling-Pathway was activated in fibroblasts of all donor groups. The Mitotic Roles of Polo Like Kinase-Pathway was inactivated in N1 and N2+. Molecular Mechanisms of Cancer were affected in fibroblasts of all donor groups. P53 was predicted to be an upstream regulator in fibroblasts of all donor groups and E2F1 in N1 and N2+. Results of the downstream analysis were senescence in N0 and N2+, transformation of cells in N0, and no significant effects in N1. Seven genes were differentially expressed in reaction to 2 Gy dependent on the donor group (LINC00601, COBLL1, SESN2, BIN3, TNFRSF10A, EEF1AKNMT, and BTG2). CONCLUSION: Our results show dose-dependent differences in the radiation response between N1/N2+ and N0. While mechanisms against genotoxic stress were activated to the same extent after a high dose in all groups, the radiation response was impaired after a low dose in N1/N2+, suggesting an increased risk for adverse effects including carcinogenesis, particularly in N2+.
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Sobreviventes de Câncer , Proteínas Imediatamente Precoces , Segunda Neoplasia Primária , Neoplasias , Adulto , Estudos de Casos e Controles , Criança , Proteínas F-Box , Fibroblastos/efeitos da radiação , Humanos , Peptídeos e Proteínas de Sinalização Intracelular , Segunda Neoplasia Primária/genética , Proteínas Nucleares , Receptores Citoplasmáticos e Nucleares , Sestrinas , Proteína Supressora de Tumor p53 , Proteínas Supressoras de TumorRESUMO
PURPOSE: Radiotherapy (RT) was identified as a risk factor for long-term cardiac effects in breast cancer patients treated until the 1990s. However, modern techniques reduce radiation exposure of the heart, but some exposure remains unavoidable. In a retrospective cohort study, we investigated cardiac mortality and morbidity of breast cancer survivors treated with recent RT in Germany. METHODS: A total of 11,982 breast cancer patients treated between 1998 and 2008 were included. A mortality follow-up was conducted until 06/2018. In order to assess cardiac morbidity occurring after breast cancer treatment, a questionnaire was sent out in 2014 and 2019. The effect of breast cancer laterality on cardiac mortality and morbidity was investigated as a proxy for radiation exposure. We used Cox Proportional Hazards regression analysis, taking potential confounders into account. RESULTS: After a median follow-up time of 11.1 years, there was no significant association of tumor laterality with cardiac mortality in irradiated patients (hazard ratio (HR) for left-sided versus right-sided tumor 1.09; 95% confidence interval (CI) 0.85-1.41). Furthermore, tumor laterality was not identified as a significant risk factor for cardiac morbidity (HR = 1.05; 95%CI 0.88-1.25). CONCLUSIONS: Even though RT for left-sided breast cancer on average incurs higher radiation dose to the heart than RT for right-sided tumors, we found no evidence that laterality is a strong risk factor for cardiac disease after contemporary RT. However, larger sample sizes, longer follow-up, detailed information on individual risk factors and heart dose are needed to assess clinically manifest late effects of current cancer therapy.
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Neoplasias da Mama , Radioterapia Conformacional , Neoplasias da Mama/epidemiologia , Neoplasias da Mama/radioterapia , Feminino , Alemanha/epidemiologia , Coração , Humanos , Radioterapia Adjuvante , Estudos RetrospectivosRESUMO
PURPOSE: About one fifth of patients with head and neck cancer are aged 70 years and older at the time of diagnosis. In these patients, risk factors (R1 status or extracapsular extension of lymph node metastases, ECE) often lead to a need for combined chemoradiotherapy (CRT) in the postoperative setting. However, there is considerable concern about the toxicity of such therapy in this age group. METHODS: Retrospective evaluation of the data of 53 patients ≥â¯70 years of age who underwent surgery in our hospital between 1999 and 2015 for tumors of the oral cavity, the oropharynx, the hypopharynx, or the larynx, who subsequently received adjuvant radiation therapy. Two younger patients (<â¯70 years) were assigned to each of the elderly patients in a matching procedure based on anatomic sublocalization and tumor stage. The total cohort was comprised of 154 patients. RESULTS: Univariate analyses revealed a statistically significant influence of many factors on overall survival (OS) and progression-free survival (PFS), including Karnofsky performance score (KPS), alcohol consumption, smoking, R status, ECE, chemotherapy, and discontinuation of RT. Younger patients had better OS and PFS compared to the elderly (pâ¯= 0.013 and 0.012, respectively). In a multivariate Cox regression, no independent influence of age on OS and PFS was found. Survival was primarily dependent on the addition of chemotherapy to radiotherapy (RT), application of the full course of RT, continued alcohol abuse, KPS, and the presence of ECE. Toxicity analysis showed a higher incidence of chronic renal failure but, generally, side effects for elderly patients were not substantially greater. CONCLUSION: Performance status and behavioral risk factors but not chronological age are crucial for the prognosis of patients who require adjuvant chemoradiation.
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Quimiorradioterapia Adjuvante , Neoplasias de Cabeça e Pescoço , Idoso , Idoso de 80 Anos ou mais , Quimiorradioterapia , Neoplasias de Cabeça e Pescoço/terapia , Humanos , Metástase Linfática , Prognóstico , Estudos RetrospectivosRESUMO
PURPOSE: The optimal treatment for clinical stage (CS) IIA/IIB seminomas is still controversial. We evaluated current treatment options. METHODS: A systematic review was performed. Only randomized clinical trials and comparative studies published from January 2010 until February 2021 were included. Search items included: seminoma, CS IIA, CS IIB and therapy. Outcome parameters were relapse rate (RR), relapse-free (RFS), overall and cancer-specific survival (OS, CSS). Additionally, acute and long-term side effects including secondary malignancies (SMs) were analyzed. RESULTS: Seven comparative studies (one prospective and six retrospective) were identified with a total of 5049 patients (CS IIA: 2840, CS IIB: 2209). The applied treatment modalities were radiotherapy (RT) (n = 3049; CS IIA: 1888, CSIIB: 1006, unknown: 155) and chemotherapy (CT) or no RT (n = 2000; CS IIA: 797, CS IIB: 1074, unknown: 129). In CS IIA, RRs ranged from 0% to 4.8% for RT and 0% for CT. Concerning CS IIB RRs of 9.5%-21.1% for RT and of 0%-14.2% for CT have been reported. 5-year OS ranged from 90 to 100%. Only two studies reported on treatment-related toxicities. CONCLUSIONS: RT and CT are the most commonly applied treatments in CS IIA/B seminoma. In CS IIA seminomas, RRs after RT and CT are similar. However, in CS IIB, CT seems to be more effective. Survival rates of CS IIA/B seminomas are excellent. Consequently, long-term toxicities and SMs are important survivorship issues. Alternative treatment approaches, e.g., retroperitoneal lymph node dissection (RPLND) or dose-reduced sequential CT/RT are currently under prospective investigation.
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Segunda Neoplasia Primária , Seminoma , Neoplasias Testiculares , Masculino , Humanos , Seminoma/radioterapia , Seminoma/tratamento farmacológico , Estudos Retrospectivos , Estudos Prospectivos , Estadiamento de Neoplasias , Recidiva Local de Neoplasia/patologia , Neoplasias Testiculares/radioterapia , Neoplasias Testiculares/tratamento farmacológico , Segunda Neoplasia Primária/patologiaRESUMO
PURPOSE: Active surveillance (AS) strategies for patients with low- and early intermediate-risk prostate cancer are still not consistently defined. Within a controlled randomized trial, active surveillance was compared to other treatment options for patients with prostate cancer. Aim of this analysis was to report on termination rates of patients treated with AS including different grade groups. METHODS: A randomized trial comparing radical prostatectomy, active surveillance, external beam radiotherapy and brachytherapy was performed from 2013 to 2016 and included 345 patients with low- and early intermediate-risk prostate cancer (ISUP grade groups 1 and 2). The trial was prematurely stopped due to slow accrual. A total of 130 patients were treated with active surveillance. Among them, 42 patients were diagnosed with intermediate-risk PCA. Reference pathology and AS quality control were performed throughout. RESULTS: After a median follow-up time of 18.8 months, 73 out of the 130 patients (56%) terminated active surveillance. Of these, 56 (77%) patients were histologically reclassified at the time of rebiopsy, including 35% and 60% of the grade group 1 and 2 patients, respectively. No patients who underwent radical prostatectomy at the time of reclassification had radical prostatectomy specimens ≥ grade group 3. CONCLUSION: In this prospectively analyzed subcohort of patients with AS and conventional staging within a randomized trial, the 2-year histological reclassification rates were higher than those previously reported. Active surveillance may not be based on conventional staging alone, and patients with grade group 2 cancers may be recommended for active surveillance in carefully controlled trials only.
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Neoplasias da Próstata/patologia , Neoplasias da Próstata/terapia , Conduta Expectante , Adolescente , Adulto , Idoso , Término Precoce de Ensaios Clínicos/estatística & dados numéricos , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Neoplasias da Próstata/classificação , Medição de Risco , Fatores de Tempo , Adulto JovemRESUMO
PURPOSE: To investigate the work situation of lung cancer survivors and to identify the factors associated with their returning to work. METHODS: Descriptive analysis and logistic regression were used to evaluate study population characteristics and independent factors of subsequently returning to work. To analyze time to return to work, Cox regression was used. RESULTS: The study sample included 232 lung cancer survivors of working age from 717 enrolled participants in the multi-center cross-sectional LARIS (Quality of Life and Psychosocial Rehabilitation in Lung Cancer Survivors) study. About 67% of the survivors were not employed during the survey. More than 51% of the survivors who were employed before their illness did not return to their work. The survivors who had returned to their careers were younger, associated with higher household income, lower fatigue score, and stable relationship and vocational training. Patients who received social service counseling showed a higher chance of regaining their career. CONCLUSIONS: Lung cancer survivors were found to be associated with a high risk of unemployment and very low professional reintegration after interruption due to illness. More comprehensive studies are needed to support lung cancer survivors and targeting of patients in need of special attention in rehabilitation that would benefit from the findings in the present study.
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Sobreviventes de Câncer/psicologia , Neoplasias Pulmonares/psicologia , Retorno ao Trabalho/tendências , Adulto , Estudos Transversais , Feminino , Alemanha , Humanos , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Inquéritos e Questionários , Sobreviventes/psicologiaRESUMO
OBJECTIVES: We developed the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up of germ cell tumours (GCT) of the testes in adult patients. We present the guideline content in 2 separate publications. The present second part summarizes therecommendations for the treatment of advanced disease stages and for the management of follow-up and late effects. MATERIALS AND METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search in March 2018), were provided. Thirty-one experts, who were entitled to vote, rated the final clinical recommendations and statements. RESULTS: Here we present the treatment recommendations separately for patients with metastatic seminoma and non-seminomatous GCT (stages IIA/B and IIC/III), for restaging and treatment of residual masses, and for relapsed and refractory disease stages. The recommendations also cover extragonadal and sex cord/stromal tumours, the management of follow-up and toxicity, quality-of-life aspects, palliative care, and supportive therapy. CONCLUSION: Physicians and other medical service providers who are involved in the diagnostics, treatment, and follow-up of GCT (all stages, outpatient and inpatient care as well as rehabilitation) are the users of the present guideline. The guideline also comprises quality indicators for measuring the implementation of the guideline recommendations in routine clinical care; these data will be presented in a future publication.
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Neoplasias Embrionárias de Células Germinativas/terapia , Tumores do Estroma Gonadal e dos Cordões Sexuais/terapia , Neoplasias Testiculares/terapia , Adulto , Assistência ao Convalescente , Humanos , Masculino , Metástase Neoplásica , Recidiva Local de Neoplasia/terapia , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/patologia , Cuidados Paliativos , Guias de Prática Clínica como Assunto , Qualidade de Vida , Neoplasias Testiculares/patologiaRESUMO
INTRODUCTION: This is the first German evidence- and consensus-based clinical guideline on diagnosis, treatment, and follow-up on germ cell tumours (GCTs) of the testis in adult patients. We present the guideline content in two publications. Part I covers the topic's background, methods, epidemiology, classification systems, diagnostics, prognosis, and treatment recommendations for the localized stages. METHODS: An interdisciplinary panel of 42 experts including 1 patient representative developed the guideline content. Clinical recommendations and statements were based on scientific evidence and expert consensus. For this purpose, evidence tables for several review questions, which were based on systematic literature searches (last search was in March 2018) were provided. Thirty-one experts entitled to vote, rated the final clinical recommendations and statements. RESULTS: We provide 161 clinical recommendations and statements. We present information on the quality of cancer care and epidemiology and give recommendations for staging and classification as well as for diagnostic procedures. The diagnostic recommendations encompass measures for assessing the primary tumour as well as procedures for the detection of metastases. One chapter addresses prognostic factors. In part I, we separately present the treatment recommendations for germ cell neoplasia in situ, and the organ-confined stages (clinical stage I) of both seminoma and nonseminoma. CONCLUSION: Although GCT is a rare tumour entity with excellent survival rates for the localized stages, its management requires an interdisciplinary approach, including several clinical experts. Quality of care is highly related to institutional expertise and can be reassured by established online-based second-opinion boards. There are very few studies on diagnostics with good level of evidence. Treatment of metastatic GCTs must be tailored to the risk according to the International Germ Cell Cancer Collaboration Group classification after careful diagnostic evaluation. An interdisciplinary approach as well as the referral of selected patients to centres with proven experience can help achieve favourable clinical outcomes.
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Neoplasias Embrionárias de Células Germinativas , Neoplasias Testiculares , Adulto , Preservação da Fertilidade , Humanos , Masculino , Estadiamento de Neoplasias , Neoplasias Embrionárias de Células Germinativas/classificação , Neoplasias Embrionárias de Células Germinativas/diagnóstico , Neoplasias Embrionárias de Células Germinativas/epidemiologia , Neoplasias Embrionárias de Células Germinativas/terapia , Guias de Prática Clínica como Assunto , Prognóstico , Neoplasias Testiculares/classificação , Neoplasias Testiculares/diagnóstico , Neoplasias Testiculares/epidemiologia , Neoplasias Testiculares/terapiaRESUMO
BACKGROUND: Exposure to ionizing radiation induces complex stress responses in cells, which can lead to adverse health effects such as cancer. Although a variety of studies investigated gene expression and affected pathways in human fibroblasts after exposure to ionizing radiation, the understanding of underlying mechanisms and biological effects is still incomplete due to different experimental settings and small sample sizes. Therefore, this study aims to identify the time point with the highest number of differentially expressed genes and corresponding pathways in primary human fibroblasts after irradiation at two preselected time points. METHODS: Fibroblasts from skin biopsies of 15 cell donors were exposed to a high (2Gy) and a low (0.05Gy) dose of X-rays. RNA was extracted and sequenced 2 h and 4 h after exposure. Differentially expressed genes with an adjusted p-value < 0.05 were flagged and used for pathway analyses including prediction of upstream and downstream effects. Principal component analyses were used to examine the effect of two different sequencing runs on quality metrics and variation in expression and alignment and for explorative analysis of the radiation dose and time point of analysis. RESULTS: More genes were differentially expressed 4 h after exposure to low and high doses of radiation than after 2 h. In experiments with high dose irradiation and RNA sequencing after 4 h, inactivation of the FAT10 cancer signaling pathway and activation of gluconeogenesis I, glycolysis I, and prostanoid biosynthesis was observed taking p-value (< 0.05) and (in) activating z-score (≥2.00 or ≤ - 2.00) into account. Two hours after high dose irradiation, inactivation of small cell lung cancer signaling was observed. For low dose irradiation experiments, we did not detect any significant (p < 0.05 and z-score ≥ 2.00 or ≤ - 2.00) activated or inactivated pathways for both time points. CONCLUSIONS: Compared to 2 h after irradiation, a higher number of differentially expressed genes were found 4 h after exposure to low and high dose ionizing radiation. Differences in gene expression were related to signal transduction pathways of the DNA damage response after 2 h and to metabolic pathways, that might implicate cellular senescence, after 4 h. The time point 4 h will be used to conduct further irradiation experiments in a larger sample.
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Fibroblastos/metabolismo , Fibroblastos/efeitos da radiação , Regulação da Expressão Gênica/efeitos da radiação , Radiação Ionizante , Transdução de Sinais/efeitos da radiação , Estudos de Casos e Controles , Células Cultivadas , Biologia Computacional/métodos , Relação Dose-Resposta à Radiação , Perfilação da Expressão Gênica , Humanos , Fatores de TempoRESUMO
PURPOSE: Biodosimetric assessment and comparison of radiation-induced deoxyribonucleic acid (DNA) double-strand breaks (DSBs) by γH2AX immunostaining in peripheral leukocytes of patients with painful heel spur after radiation therapy (RT) with orthovoltage Xrays or a 6-MV linear accelerator (linac). The treatment response for each RT technique was monitored as a secondary endpoint. PATIENTS AND METHODS: 22 patients were treated either with 140-kV orthovoltage Xrays (nâ¯= 11) or a 6-MV linac (nâ¯= 11) with two weekly fractions of 0.5â¯Gy for 3 weeks. In both scenarios, the dose was prescribed to the International Commission on Radiation Units and Measurements (ICRU) dose reference point. Blood samples were obtained before and 30â¯min after the first RT session. γH2AX foci were quantified by immunofluorescence microscopy to assess the yield of DSBs at the basal level and after radiation exposure ex vivo or in vivo. The treatment response was assessed before and 3 months after RT using a five-level functional calcaneodynia score. RESULTS: RT for painful heel spurs induced a very mild but significant increase of γH2AX foci in patients' leukocytes. No difference between the RT techniques was observed. High and comparable therapeutic responses were documented for both treatment modalities. This trial was terminated preliminarily after an interim analysis (22 patients randomized). CONCLUSION: Low-dose RT for painful heel spurs with orthovoltage Xrays or a 6-MV linac is an effective treatment option associated with a very low and comparable radiation burden to the patient, as confirmed by biodosimetric measurements.
Assuntos
Quebras de DNA de Cadeia Dupla/efeitos da radiação , Esporão do Calcâneo/radioterapia , Leucócitos/efeitos da radiação , Radioterapia/efeitos adversos , Adulto , Idoso , Feminino , Histonas/análise , Humanos , Masculino , Pessoa de Meia-Idade , Aceleradores de Partículas/instrumentação , Radioterapia/instrumentação , Dosagem RadioterapêuticaRESUMO
PURPOSE: To investigate the efficacy and toxicity of cetuximab when added to radiochemotherapy for unresectable esophageal cancer. METHODS: This randomized phase 2 trial (clinicaltrials.gov, identifier NCT01787006) compared radiochemotherapy plus cetuximab (arm A) to radiochemotherapy (arm B) for unresectable esophageal cancer. Primary objective was 2year overall survival (OS). Arm A was considered insufficiently active if 2year OS was ≤40% (null hypothesisâ¯= H0), and promising if the lower limit of the 95% confidence interval was >45%. If that lower limit was >40%, H0 was rejected. Secondary objectives included progression-free survival (PFS), locoregional control (LC), metastases-free survival (MFS), response, and toxicity. The study was terminated early after 74 patients; 68 patients were evaluable. RESULTS: Two-year OS was 71% in arm A (95% CI: 55-87%) vs. 53% in arm B (95% CI: 36-71%); H0 was rejected. Median OS was 49.1 vs. 24.1 months (pâ¯= 0.147). Hazard ratio (HR) for death was 0.60 (95% CI: 0.30-1.21). At 2 years, PFS was 56% vs. 44%, LC 84% vs. 72%, and MFS 74% vs. 54%. HRs were 0.51 (0.25-1.04) for progression, 0.43 (0.13-1.40) for locoregional failure, and 0.43 (0.17-1.05) for distant metastasis. Overall response was 81% vs. 69% (pâ¯= 0.262). Twenty-six and 27 patients, respectively, experienced at least one toxicity grade ≥3 (pâ¯= 0.573). A significant difference was found for grade ≥3 allergic reactions (12.5% vs. 0%, pâ¯= 0.044). CONCLUSION: Given the limitations of this trial, radiochemotherapy plus cetuximab was feasible. There was a trend towards improved PFS and MFS. Larger studies are required to better define the role of cetuximab for unresectable esophageal cancer.
Assuntos
Antineoplásicos Imunológicos/uso terapêutico , Cetuximab/uso terapêutico , Quimiorradioterapia , Neoplasias Esofágicas/terapia , Adulto , Idoso , Idoso de 80 Anos ou mais , Antineoplásicos Imunológicos/efeitos adversos , Cetuximab/efeitos adversos , Quimiorradioterapia/efeitos adversos , Intervalo Livre de Doença , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Intervalo Livre de ProgressãoRESUMO
Hepatocellular carcinomas (HCCs) are highly malignant primary liver cancers with poor prognosis and limited treatment options in advanced stages of disease. Treatment of HCC requires interdisciplinary discussion and multimodal therapy approaches. Beside established loco-regional and systemic therapies, stereotactic body radiation therapy (SBRT) gained increasing importance over recent years. First results of early clinical studies indicate high rates of local control with a good safety profile. In the present work, we evaluated our single center experiences with SBRT in patients with advanced HCCs.Ten patients with 16 SBRTs were included and retrospectively analyzed in this case collection. All patients presented in advanced tumor stages with vascular invasion and/or metastases, but preserved liver function. Two patients were treated only with SBRT, two after TACE and six patients received SBRT in addition to systemic therapy. In most of the cases SBRT were applied to intrahepatic lesions. Large tumor thromboses, lymph nodes as well as bone metastases were irradiated in one, three and five fractions with a median overall dose of 38âGy. We observed a good local tumor control with a good safety profile in all cases. No severe complications occurred in combination to sequential as well as additive approach to loco-regional or systemic treatments.In conclusion, our experiences confirm results of early clinical studies indicating safe use and good local control rates also in advanced stages of HCC with preserved liver function.
Assuntos
Carcinoma Hepatocelular/terapia , Neoplasias Hepáticas/terapia , Radiocirurgia , Quimioembolização Terapêutica , Terapia Combinada , Humanos , Estadiamento de Neoplasias , Estudos Retrospectivos , Resultado do TratamentoAssuntos
Carcinoma de Células Escamosas , Neoplasias Esofágicas , Humanos , Neoplasias Esofágicas/terapia , Neoplasias Esofágicas/patologia , Carcinoma de Células Escamosas/secundário , Carcinoma de Células Escamosas/terapia , Carcinoma de Células Escamosas/cirurgia , Carcinoma de Células Escamosas/patologia , Terapia Combinada , Masculino , Feminino , Pessoa de Meia-Idade , Idoso , Carcinoma de Células Escamosas do Esôfago/secundário , Carcinoma de Células Escamosas do Esôfago/terapia , Estadiamento de NeoplasiasRESUMO
PURPOSE: This retrospective study aimed to evaluate the stability and fracture rates of osteolytic spinal bone metastases (SBM) in elderly patients following palliative radiotherapy (RT) and to derive prognostic factors for stability and survival. METHODS: A total of 322 patients aged at least 70 years received palliative RT at two major German academic medical centers or at the German Cancer Research Center. Stability assessment was based on the validated Taneichi score prior to RT and at 3 and 6 months after RT. The survival time following RT was assessed, and prognostic factors for stability and survival were analyzed. RESULTS: Prior to RT, 183 patients (57%) exhibited unstable SBM and 68 patients (21%) pathological fractures. At 3 and 6 months after RT, significant recalcification and stabilization were evident in 19% (23/118) and 40% (31/78) of surviving patients, respectively. Only 17 patients (5%) experienced new pathological fractures following RT. Tumor histology was found to significantly influence stabilization rates with only breast cancer patients exhibiting increased stabilization compared to patients with other histologies. The median survival time and 6month survival rates following RT were 5.4 months (95% confidence interval 4.4-7.2 months) and 48%, respectively. The patients' performance status was found to be the strongest predictor for survival after RT in this patient cohort; further factors demonstrating a significant association with survival were the application of systemic treatment, the number of SBM and the primary tumor histology. To analyze the influence of age on survival after RT, study patients were stratified into 3 age groups (i.e., 70-74 years, 75-79 years, and ≥80 years). The subgroup of patients aged at least 80 years showed a strong trend towards a worse survival time following RT compared to younger patients (i.e., 6month survival rate 39% vs. 51%; pâ¯= 0.06, log-rank test). CONCLUSIONS: Prognostic factors influencing overall survival such as performance status and histology should guide the choice for palliative RT for SBM. Strongly hypofractionated RT regimes may be advisable for most elderly patients considering the overall poor prognosis in order to reduce hospitalization times.