Major breakthroughs in lung cancer adjuvant treatment: Looking beyond the horizon.

We are witnessing a silent revolution in the treatment of early stage non-small cell lung cancer (NSCLC), with a series of practice-changing clinical trials enriching the therapeutic perspectives of lung cancer patients with potentially curable disease. The ADAURA study marked the advent of precision medicine and biomarker testing to the early stages setting. The IMPower-010 trial interrupted the negative trend of adjuvant lung cancer immunotherapy, paving the way to the application of immune-checkpoint inhibition in the resected disease. The ITACA trial definitively established no role for tailored adjuvant chemotherapy in NSCLC, while the Lung Art data questioned the efficacy of post-operative radiotherapy for pN2 resected disease. Growing evidence is supporting MRD as effective adjuvant prognostic biomarker to stratify disease's recurrence risk after radical interventions and select best candidates to the adjuvant strategies. This work summarizes the recent major breakthroughs in lung cancer adjuvant treatment, and provides a snapshot of the current real-world scenario, discussing the upcoming challenges and opportunities featuring the clinical management of early stage NSCLC patients.

A systematic review of phase II trials exploring anti-PD-1/PD-L1 combinations in patients with solid tumors.

BACKGROUND: A high number of combinations of PD-1/PD-L1 inhibitors with other anti-cancer therapies are in clinical development. The usefulness of phase II trials in evaluating their efficacy and safety is unclear. MATERIALS AND METHODS: We performed a systematic search on PubMed and Cochrane Library for phase II trials of PD-1/PD-L1 inhibitors in combination with other anti-cancer therapies (systemic therapy and/or radiotherapy) published between January 1st 2018 and December 31st 2020. Study design, primary endpoint and main outcomes were registered for each paper. RESULTS: 119 articles reporting on 65 regimens were included in our analysis. Backbone agents were more frequently PD-1 inhibitors (pembrolizumab = 47, nivolumab = 41, camrelizumab = 3) followed by anti-PD-L1 (durvalumab = 19, atezolizumab = 6, avelumab = 3). Therapeutic partners were other immunotherapeutic agents (n = 46), targeted therapies (n = 40), chemotherapy (n = 22) or radiotherapy (n = 11). The majority of articles reported on single-arm trials (n = 87, 73%) and response rate was the most frequent primary endpoint (n = 69, 58%). Objective responses, registered in 109 (92%) articles, ranged between 0% and 91%. The incidence of grade 3 or higher treatment-related adverse events, clearly reported in 97 (82%) articles, spanned from 0 to 100%. Five combinations received regulatory approval by Food and Drug Administration or European Medicine Agency for 9 different indications, based on the results of a phase II trial (n = 3) or on a confirmatory phase III trial (n = 6). CONCLUSIONS: The landscape of phase II trials evaluating PD-1/PD-L1 inhibitors with other anticancer therapies is heterogeneous. Combinations of two immunotherapeutic agents have been the most investigated. Only a minority of indications (8%) granted regulatory approval.

Treatment stage migration and treatment sequences in patients with hepatocellular carcinoma: drawbacks and opportunities.

PURPOSE: This retrospective analysis focuses on treatment stage migration in patients with hepatocellular carcinoma (HCC) to identify successful treatment sequences in a large cohort of real-world patients. METHODS: 1369 HCC patients referred from January 1993 to January 2020 to the tertiary center of the Heidelberg University Hospital, Germany were analyzed for initial and subsequent treatment patterns, and overall survival. RESULTS: The most common initial treatment was transarterial chemoembolization (TACE, n = 455, 39.3%) followed by hepatic resection (n = 303, 26.1%) and systemic therapy (n = 200, 17.3%), whereas the most common 2nd treatment modality was liver transplantation (n = 215, 33.2%) followed by systemic therapy (n = 177, 27.3%) and TACE (n = 85, 13.1%). Kaplan-Meier analysis revealed by far the best prognosis for liver transplantation recipients (median overall survival not reached), followed by patients with hepatic resection (11.1 years). Patients receiving systemic therapy as their first treatment had the shortest median overall survival (1.7 years; P < 0.0001). When three or more treatment sequences preceded liver transplantation, patients had a significant shorter median overall survival (1st seq.: not reached; 2nd seq.: 12.4 years; 3rd seq.: 11.1 years; beyond 3 sequences: 5.5 years; P = 0.01). CONCLUSION: TACE was the most common initial intervention, whereas liver transplantation was the most frequent 2nd treatment. While liver transplantation and hepatic resection were associated with the best median overall survival, the timing of liver transplantation within the treatment sequence strongly affected median survival.

Acute lymphoblastic leukemia-like treatment regimen provides better response in mixed phenotype acute leukemia: a comparative study between adults and pediatric MPAL patients.

Mixed phenotype acute leukemia (MPAL) is a rare type of leukemia with a limited number of studies conducted to characterize its clinical spectrum and most importantly the best treatment modality. MPAL blasts show more than one phenotype either myeloid/monocytic with T- or B-lymphoid or extremely rare triple lineage associated phenotypic markers. This study aimed to characterize MPAL cases with special emphasis on comparing adult and pediatric age groups, exploring treatment regimens, and clinical outcome. Among 2571 acute leukemia patients, 102 MPAL cases fulfilling the 2008/2016 WHO diagnostic criteria of MPAL were recruited in the study. The incidence of MPAL was 4% of acute leukemia patients. Pediatric cases were 54 (53%) while adults were 48/102 (47%). Myeloid/B-lymphoid phenotype was found in 86/102 (84%), with BCR-ABL fusion gene transcript detected in 14/102(13.7%) patients. ALL-like treatment showed better response rates as compared with the myeloid based regimen (p = 0.001). MPAL behaves in a manner that resembles in clinical features, their lymphoid progenitor counterpart leukemias both in adults and pediatric patients with superior treatment response to ALL-like regimen, especially in adults.

Una visión integral del cáncer (II). Campos de estudio y biomarcadores emergentes / An integral view of cancer (II). Fields of investigation and emerging biomarkers

El mundo de la Patología cobra sentido de la mano de la Oncología Clínica, donde técnicas y tratamientos, biomarcadores y anticuerpos, comparten el objetivo de hallar nuevas posibilidades de intervención, más eficaces, menos agresivas y más integrales. En esta búsqueda, la evidencia muestra como la mecánica tisular afecta la carcinogénesis y como la heterogeneidad tumoral depende de la alteración metabólica del estroma y del efecto Warburg de las células malignas, regulado directamente por PD-1 y diana del tratamiento inmunoterápico. Proliferación y apoptosis dependen de la disfunción mitocondrial de la célula tumoral que determina el grado de quimio- y radiorresistencia. El estado de la microbiota intestinal determina la respuesta inmune, la estructura del microambiente del tumor y la respuesta al tratamiento oncológico, y el receptor de la vitamina D permite la reprogramación del estroma tumoral. En la actualidad, la colaboración entre los mundos de la investigación básica y clínica establece como zonas de desarrollo próximo el estudio del microambiente tumoral y la mecanoterapia molecular, el metabolismo y la inmunoterapia, la mitocondria y la oncogénesis, la microbiota y la quimioterapia, el eje psiconeuroendocrino y el desequilibrio homeostático, la epigenética y las posibilidades de reprogramación del fenotipo tumoral. De todos estos campos de conocimiento surgen nuevos biomarcadores, pronósticos y predictivos, que revisamos en este artículo al servicio de nuevas posibilidades de intervención terapéutica

Pathology and clinical oncology work hand in hand so that techniques and treatments, biomarkers and antibodies share the common goal of identifying integral new treatment regimens that are more effective and less aggressive. Evidence shows how tissue mechanics affect carcinogenesis and that tumor heterogeneity depends on metabolic stromal alteration and the Warburg effect of malignant cells, regulated directly by PD-1, becoming a target for immunotherapy. Proliferation and apoptosis depend on mitochondrial dysfunction in tumor cells, determining the grade of chemo/radio-resistance. The status of intestinal microbiota regulates immune response, tumor microenvironment structure and oncologic treatment response, whilst the Vitamin D receptor allows reprogramming of tumor stroma. Current collaboration between basic and clinical research paves the way for future investigation into areas such as tumor microenvironment and molecular mechanotherapy, metabolism and immunotherapy, mitochondria and oncogenesis, microbiota and chemotherapy, psychoneuroendocrine axis and homeostatic imbalance, epigenetics and reprogramming possibilities of the tumor phenotype. We review new prognostic and predictive biomarkers emerging from these fields of knowledge, opening up new therapeutic possibilities

Treatment-related mortality in children with cancer: Prevalence and risk factors.

AIM: Intensive treatment regimens have contributed to a marked increase in childhood cancer survival rates. Death due to treatment-related adverse effects becomes an increasingly important area to further improve overall survival. In this study, we examined 5-year survival in children with cancer to identify risk factors for treatment-related mortality (TRM). METHODS: All children (aged <18 years at diagnosis) diagnosed with cancer in 2 Dutch university hospitals between 2003 and 2013 were included, survival status was determined and causes of death were analysed. Various demographic and treatment factors were evaluated, for which a multivariable competing risks analysis was performed. RESULTS: A total of 1764 patients were included; overall 5-year survival was 78.6%. Of all 378 deaths, 81 (21.4%) were treatment-related, with infection being responsible for more than half of these deaths. Forty percent of TRM occurred in the first three months after initial diagnosis. Factors associated with TRM in the multivariable competing risks analysis were diagnosis of a haematological malignancy, age at diagnosis <1 year and receipt of allogeneic haematopoietic stem cell transplantation. In children suffering from haematological malignancies, TRM accounted for 56.3% of 103 deaths. CONCLUSION: Over one in five deaths in children with cancer death was related to treatment, mostly due to infection. In children suffering from a haematological malignancy, more children died due to their treatment than due to progression of their disease. To further increase overall survival, clinical and research focus should be placed on lowering TRM rates without compromising anti-tumour efficacy. The findings presented in this study might help identifying areas for improvement.

Attributable Failure of First-line Cancer Treatment and Incremental Costs Associated With Smoking by Patients With Cancer.

Importance: Previous studies have shown that continued smoking among patients with cancer can increase overall and cancer-specific mortality, risk for second primary cancer, and risk for toxic effects of cancer treatment. To our knowledge, there have been no efforts to estimate additional costs for cancer treatment attributed to smoking. Objective: To model attributable incremental costs of subsequent cancer treatment associated with continued smoking by patients with cancer. Design, Setting, and Participants: For this economic evaluation, a model was developed in 2018 using data from a 2014 US Surgeon General's report that considered expected failure rates of first-line cancer treatment in nonsmoking patients, smoking prevalence, odds ratio of first-line cancer treatment failure attributed to smoking compared with nonsmoking, and cost of cancer treatment after failure of first-line cancer treatment. Main Outcomes and Measures: Attributable failures of first-line cancer treatment and incremental cost for subsequent treatment associated with continued smoking among patients with cancer. Results: Attributable treatment failures were higher under conditions in which high first-line cure rates were expected in nonsmoking patients compared with conditions in which low cure rates were expected. Peak attributable failures occurred under the conditions in which expected cure rates among nonsmoking patients ranged from 50% to 65%. Under the conditions of a 30% expected treatment failure rate among nonsmoking patients, 20% smoking prevalence, 60% increased risk of failure of first-line cancer treatment, and $100 000 mean added cost of treating a first-line cancer treatment failure, the additional incremental cost per 1000 total patients was estimated to be $2.1 million, reflecting an additional cost of $10 678 per smoking patient. Extrapolation of cost to 1.6 million patients with cancer diagnosed annually reflects a potential $3.4 billion in incremental cost. Conclusions and Relevance: The findings suggest that continued smoking among patients with cancer and the increase in attributable first-line cancer treatment failure is associated with significant incremental costs for subsequent cancer treatments. Additional work appears to be needed to identify optimal methods to mitigate these incremental costs.

Protocolos de tomografía computarizada empleados en la estadificación del carcinoma broncopulmonar: resultados de una encuesta a nivel nacional / Computed tomography protocols used in staging bronchopulmonary carcinoma: results of a national survey

Objetivos. Conocer los protocolos de exploración de tomografía computarizada empleados en la estadificación del carcinoma broncopulmonar en España. Material y métodos. Mediante correo electrónico se enviaron encuestas a radiólogos de 129 hospitales. Las encuestas incluían preguntas sobre la organización del servicio, tipo y marca del escáner, extensión del estudio, técnica empleada y protocolo de administración del contraste. Resultados. Cincuenta y nueve hospitales respondieron con datos de 91 equipos. La mayoría de los hospitales fueron universitarios con organización por órganos y sistemas. Los modelos empleados incluyen cuatro marcas, el 68% de 16 o 64 detectores. En un 61% de los hospitales solo se modificaba la dosis de contraste en pacientes con pesos extremos y en el 22% no existía individualización. La mayoría de los hospitales realizaba un estudio del tórax y abdomen superior con contraste, un 42,4% con una única adquisición toracoabdominal y un 55,9% con dos adquisiciones independientes, existiendo relación significativa de ambos protocolos con dos marcas de escáner y con el carácter universitario del hospital. Los parámetros técnicos más empleados fueron 120kV con modulación de dosis y miliamperaje variable. Conclusión. El tipo de escáner empleado, la extensión del estudio y los parámetros técnicos empleados en la estadificación del cáncer broncopulmonar muestran escasa variabilidad entre los hospitales. La mayoría individualiza la dosis de contraste solo en pesos extremos. Hay una amplia división entre el empleo de una o dos adquisiciones para el tórax y el abdomen, existiendo relación entre número de adquisiciones con la marca del escáner y el carácter universitario del hospital (AU)

Objectives. To know the protocols used for staging bronchopulmonary carcinoma by computed tomography in Spain. Material and methods. Radiologists in 129 hospitals were sent email questionnaires about the organization of their department, scanner type and manufacturer, study extension, techniques employed, and protocol for administering contrast material. Results. A total of 109 hospitals responded with data from 91 teams. Most hospitals were affiliated with a university, and most departments were organized by organ-systems. Scanners were from four manufacturers, and 68% had either 16 or 64 detectors. In 61% of the hospitals, the dose of contrast agent is modified only in patients with extreme body weights, and in 22% the dose is not individualized. Most hospitals do contrast-enhanced studies of the chest and upper abdomen, 42.4% through a single thoracoabdominal acquisition and 55.9% through independent chest and abdominal acquisitions; there was a significant association between these approaches and the scanner manufacturer's protocols and whether the hospital was affiliated with a university. The most commonly used technical parameters were 120kV with dose modulation and variable milliamperage. Conclusion. There is very little variability among hospitals in the type of scanner used, the study extension, and the technical parameters used to stage bronchopulmonary carcinoma. Most centers individualize the dose of contrast agent only in extreme weights. There is a broad division between using one or two acquisitions to image the thorax and abdomen, and the number of acquisitions is related to the scanner manufacturer and whether the hospital is affiliated with a university (AU)

Radioterapia intraoperatoria de la mama con Intrabeam®: experiencia inicial en nuestro centro / Intraoperative radiotherapy of the breast with Intrabeam®: initial experience at our center

Objetivo. La intraoperative radiotherapy (IORT, «radioterapia intraoperatoria») en pacientes seleccionadas con cáncer de mama permite un tratamiento corto y preciso durante la cirugía conservadora sobre el lecho tumoral in situ. Presentamos nuestra experiencia inicial de IORT con dispositivo Intrabeam®. Pacientes y métodos. Se seleccionaron inicialmente 120 pacientes con cáncer de mama para IORT con Intrabeam® según protocolo TARGIT-A, desde enero de 2013 hasta febrero de 2015. Las indicaciones fueron: candidatas a cirugía conservadora, mayores de 45 años, diagnóstico histológico de carcinoma ductal infiltrante≤3cm hormonodependiente y axila clínica, ecográfica e histológicamente negativa. Resultados. De las pacientes seleccionadas, 34 (28%) no recibieron IORT debido al tamaño de la cavidad quirúrgica (28 casos) o problemas técnicos (6 casos). Finalmente, 86 pacientes (72%) recibieron IORT. La edad media fue de 64 años (DE±8,4). En 22 pacientes (26%) fue preciso administrar radioterapia externa a toda la mama. Trece pacientes (15%) tuvieron complicaciones: 3 casos de seroma que precisaron de más de 3 punciones para resolución (4%), 6 casos de absceso-mastitis (7%), 2 casos de hematoma (2%) y 2 casos de dehiscencia parcial de la herida quirúrgica (2%). No hubo toxicidad grave (grado iii-iv). El resultado estético fue bueno o muy bueno en el 87% de las pacientes (75). Conclusión. La IORT con Intrabeam® es una alternativa segura y bien tolerada frente a la radioterapia externa en pacientes seleccionadas, con un buen resultado estético a corto plazo (AU)

Objective. Intraoperative radiotherapy (IORT) in selected patients with breast cancer allows a short and precise treatment on the tumor bed in situ during conservative surgery. We present our initial experience of IORT with the Intrabeam® device. Patients and methods. From January 2013 to February 2015, 120 patients with breast cancer were pre-selected for IORT with Intrabeam® according to the TARGIT-A protocol. The indications were as follows: candidates for conservative surgery, age older than 45 years, a histological diagnosis of hormone-dependent infiltrating ductal carcinoma≤3cm and absence of axillary involvement on physical, ultrasound and histological examination. Results. Among the selected patients, 34 (28%) did not receive IORT due to the size of the surgical cavity (28 patients) or technical problems (6 patients). Finally, 86 patients (72%) received IORT. The average age was 64 years (SD±8.4). In 22 patients (26%), it was necessary to administer external beam radiotherapy to the whole breast. Thirteen patients (15%) had complications: 3 cases of seroma requiring more than 3 attempts for resolution (4%), 6 cases of abscess-mastitis (7%), 2 cases of hematoma (2%) and 2 cases of partial dehiscence of the surgical wound (2%). There was no severe toxicity (grade iii-iv). The aesthetic result was good or very good in 87% of the patients (n=75). Conclusion. IORT with Intrabeam® is a safe and well tolerated alternative versus external radiotherapy in selected patients and provides a good short-term aesthetic result (AU)

Biopsia del ganglio centinela y quimioterapia neoadyuvante en pacientes con cáncer de mama: nuestra experiencia / Sentinel lymph node biopsy and neoadjuvant chemotherapy in breast cancer patients: our experience

Objetivo. Revisar nuestra experiencia en la biopsia selectiva del ganglio centinela (BGC) en pacientes con cáncer de mama operable tratadas con quimioterapia neoadyuvante (QTN). Material y métodos. Estudio prospectivo, enero de 2008/diciembre de 2014, 235 BGC en pacientes con cáncer de mama infiltrante T1-3/N0-1, tratadas con epirrubicina/ciclofosfamida, docetaxel y trastuzumab en Her2/neu positivas. El estatus axilar se estableció por exploración física, ecografía axilar y punción de ganglios sospechosos. El día antes de la cirugía se inyectaron periareolarmente 74-111 MBq de 99mTc-nanocoloide de albúmina. Al finalizar el tratamiento se realizó BGC y linfadenectomía axilar. El GC se analizó por cortes de congelación, hematoxilina-eosina, inmunohistoquímica o one-step nucleic acid amplification. Se determinaron tasa de identificación (Id.GC) y falsos negativos (FN). Resultados. Grupo I BGC pre-QTN pacientes cN0 de inicio: n = 73, Id.GC 97,2% (IC 95% 90,5-99,2). Grupo II 2.a BGC pos-QTN pacientes pN1(gc) de inicio: n = 31, Id.GC 61,3% (IC 95% 43,8-76,3), FN 18,2% (IC 95% 5,1-47,7). Grupo III BGC pos-QTN pacientes cN0 de inicio: n = 54, Id.GC 96,3% (IC 95% 87,5-99,0), FN 9,5% (IC 95% 2,7-28,9). Grupo IV BGC pos-QTN pacientes cN1 de inicio, ycN0 posneoadyuvancia: n = 77, Id.GC 83,1% (IC 95% 73,2-89,8), FN 8,3% (IC 95% 2,9-21,8). Conclusiones. La identificación de la BGC pre-QTN es excelente. En pacientes pN1(gc) al diagnóstico, una 2.a BGC pos-QTN no es válida para su aplicación clínica. La BGC pos-QTN puede realizarse con fiabilidad en pacientes cN0 y cN1 de inicio, con axila clínicamente negativa al finalizar la neoadyuvancia (ycN0), y linfadenectomía axilar si el resultado del GC es positivo o no se identifica en la cirugía, en el ámbito de un equipo multidisciplinar con experiencia (AU)

Aim. To analyze our experience of sentinel lymph node biopsy (SLNB) in patients with operable breast cancer treated with neoadjuvant chemotherapy (NAC). Material and methods. A prospective study was conducted between January 2008 and December 2014 in 235 SLNB in patients with infiltrating breast carcinoma T1-3/N0-1 treated with epirubicin/cyclophosphamide, docetaxel and trastuzumab in Her2/neu-positive patients. Axillary evaluation included physical examination and ultrasound, with guided core needle biopsy of any suspicious lymph nodes. The day before surgery, 74-111 MBq of 99mTc-albumin nanocolloid was injected periareolar. Following NAC, patients underwent SLNB and axillary lymph node dissection. SLN were examined with hematoxylin-eosin staining and immunohistochemical analysis or one-step nucleic acid amplification. The identification rate (IR) and false-negative rate (FNR) were determined. Results. Group I SLNB pre-NAC in patients cN0 at diagnosis: n = 73, IR 97.2% (95%CI: 90.5-99.2). Group II 2nd SLNB pos-NAC in patients pN1(sn) at diagnosis: n = 31, IR 61.3% (95%CI: 43.8-76.3), FNR 18.2% (95%CI: 5.1-47.7). Group III SLNB pos-NAC in patients cN0 at diagnosis: n = 54, IR 96.3% (95%CI: 87.5-99.0), FNR 9.5% (95%CI: 2.7-28.9). Group IV SLNB pos-NAC in patients cN1 at diagnosis and ycN0 post-treatment: n = 77, IR 83.1% (95%CI: 73.2-89.8), FNR 8.3% (95%CI: 2.9-21.8). Conclusions. The detection rate for SLNB prior to NAC is excellent. A second SLNB after NAC in women with a positive SLN at diagnosis is not useful. SLNB after NAC is feasible in cN0 and cN1 patients at diagnosis, clinically axillary node-negative after therapy (ycN0), with subsequent axillary lymph node dissection if the SLNB is positive or not identified during surgery, when performed by an experienced multidisciplinary team (AU)

Use of treatment information from a state central cancer registry in prostate cancer research.

A method was developed to categorize prostate cancer treatments for epidemiologic and outcomes studies. A total of 60,497 prostate cancer cases from the Florida Cancer Data System diagnosed between 2001 and 2007 were used. The classification has the following properties. First, the treatments classified in the same group are clinically comparable and capture all prostate cancer treatments or combinations of treatments (exhaustive classification). Second, the grouping was set up in a way that each patient is captured in only 1 treatment category without leaving out any patient due to treatment type (mutually exclusive categories). The prostate cancer cases were initially categorized into 14 combinations of treatment, which were then collapsed into 8 broader groups in order to maintain a large sample size for all groups, with treatments remaining clinically comparable within a group.

[Assessment of functioning in patients with head and neck cancer based on the international classification of functioning, disability and health (ICF)]. / Beurteilung von Funktionsfähigkeit bei Patienten mit Kopf-Hals-Tumoren, auf Basis der Internationalen Klassifikation für Funktionsfähigkeit, Behinderung und Gesundheit (ICF).

The article approaches with the question how preservation of function after treatment of head and neck cancer (HNC) can be defined and measured across treatment approaches. On the basis of the "International Classification of Functioning, Disability and Health (ICF)" a series of efforts are summarized how all relevant aspects of the interdisciplinary team can be integrated into a common concept.Different efforts on the development, validation and implementation of ICF Core Sets for head and neck cancer (ICF-HNC) are discussed. The ICF-HNC covers organ-based problems with food ingestion, breathing, and speech, as well as psychosocial difficulties.Relationships between the ICF-HNC and well-established outcome measures are illustrated. This enables the user to integrate different aspects of functional outcome into a consolidated approach towards preservation/rehabilitation of functioning after HNC - applicable for a variety of treatment-approaches and health-professions.

Maintenance chemotherapy: an evolving and increasingly acceptable strategy in cancer management.

Individual randomized phase 3 trials and meta-analyses of previously published studies have provided support for the general concept of the clinical utility of extending the duration of antineoplastic drug therapy in an effort to prolong ("maintain") a favorable clinical state. This commentary briefly reviews data from several of these reports.