International Cost-Effectiveness Analysis of Durvalumab in Stage III Non-Small Cell Lung Cancer.

Importance: Standard of care for unresectable locally advanced non-small cell lung cancer (NSCLC) involves definitive chemoradiotherapy followed by maintenance therapy with durvalumab. However, the cost of durvalumab has been cited as a barrier to its use in various health systems. Objective: To evaluate the cost-effectiveness of durvalumab vs placebo as maintenance therapy in patients with unresectable stage III NSCLC from 4 international payer perspectives (US, Brazil, Singapore, and Spain). Design, Setting, and Participants: In this economic evaluation, a Markov model was designed to compare the lifetime cost-effectiveness of maintenance durvalumab for unresectable stage III NSCLC with that of placebo, using 5-year outcomes data from the PACIFIC randomized placebo-controlled trial. Individual patient data were extracted from the PACIFIC, KEYNOTE-189, ADAURA, ALEX, and REVEL randomized clinical trials to develop a decision-analytic model to determine the cost-effectiveness of durvalumab compared with placebo maintenance therapy over a 10-year time horizon. Direct costs, adverse events, and patient characteristics were based on country-specific payer perspectives and demographic characteristics. The study was conducted from June 1, 2022, through December 27, 2023. Main Outcomes and Measures: Life-years, quality-adjusted life years (QALYs), lifetime costs, and incremental cost-effectiveness ratios (ICERs) were estimated at country-specific willingness-to-pay thresholds ([data reported in US$] US: $150 000 per QALY; Brazil: $22 251 per QALY; Singapore: $55 288 per QALY, and Spain: $107 069 per QALY). One-way and probabilistic sensitivity analyses were performed to account for parameters of uncertainty. A cost-threshold analysis was also performed. Results: The US base-case model found that treatment with durvalumab was associated with an increased cost of $114 394 and improved effectiveness of 0.50 QALYs compared with placebo, leading to an ICER of $228 788 per QALY. Incremental cost-effectiveness ratios, according to base-case models, were $141 146 for Brazil, $153 461 for Singapore, and $125 193 for Spain. Durvalumab price adjustments to the PACIFIC data improved cost-effectiveness in Singapore, with an ICER of $45 164. The model was most sensitive to the utility of durvalumab. Conclusions and Relevance: In this cost-effectiveness analysis of durvalumab as maintenance therapy for unresectable stage III NSCLC, the therapy was found to be cost-prohibitive from the perspective of various international payers according to country-specific willingness-to-pay thresholds per QALY. The findings of the study suggest that discounted durvalumab acquisition costs, as possible in Singapore, might improve cost-effectiveness globally.

Ibero-American Consensus Review and Incorporation of New Biomarkers for Clinical Practice in Colorectal Cancer.

Advances in genomic technologies have significantly improved the management of colorectal cancer (CRC). Several biomarkers have been identified in CRC that enable personalization in the use of biologic agents that have shown to enhance the clinical outcomes of patients. However, technologies used for their determination generate massive amounts of information that can be difficult for the clinician to interpret and use adequately. Through several discussion meetings, a group of oncology experts from Spain and several Latin American countries reviewed the latest literature to provide practical recommendations on the determination of biomarkers in CRC based on their clinical experience. The article also describes the importance of looking for additional prognostic biomarkers and the use of histopathology to establish an adequate molecular classification. Present and future of immunotherapy biomarkers in CRC patients are also discussed, together with several techniques for marker determination, including liquid biopsy, next-generation sequencing (NGS), polymerase chain reaction (PCR), and fecal immunohistochemical tests. Finally, the role of Molecular Tumor Boards in the diagnosis and treatment of CRC is described. All of this information will allow us to highlight the importance of biomarker determination in CRC.

Guidelines for biomarker testing in colorectal carcinoma (CRC): a national consensus of the Spanish Society of Pathology (SEAP) and the Spanish Society of Medical Oncology (SEOM).

This consensus statement, conceived as a joint initiative of the Spanish Society of Pathology and the Spanish Society of Medical Oncology, makes diagnostic and treatment recommendations for the management of patients with hereditary, localised and advanced CRC based on the current scientific evidence on biomarker use. This consensus statement thus provides an opportunity to improve healthcare efficiency and resource use, which will benefit these patients. Based on the currently available data on this subject, this expert group recommends testing for microsatellite instability (MSI) in patients with localised CRC, as this is a strong predictive factor for deciding on adjuvant treatment. However, although the ColoPrint(®) and Oncotype Dx(®) gene expression signatures have been shown to have prognostic value, no consensus yet exists concerning their use in clinical practice. For advanced CRC, it is essential to test for KRAS mutation status before administering an anti-EGFR treatment, such as cetuximab or panitumumab. However, testing for other biomarkers, such as BRAF, EGFR, PI3K and PTEN mutations, should not be done routinely, because this does not influence treatment planning at the present time. Other important issues addressed include organisational requirements and the quality controls needed for proper testing of these biomarkers as well as the legal implications to be borne in mind when testing some biomarkers.

The multimodal management of locally advanced N2 non-small cell lung cancer: is there a role for surgical resection? A single institution's experience.

BACKGROUND: The management of operable locally advanced N2 non-small cell lung cancer (NSCLC) is a controversial topic. Concurrent chemoradiation (CT-RT) is considered the standard of care for inoperable or unresectable patients, but the role of trimodality treatment remains controversial. We present our institution's experience with the management of stage III (N2) NSCLC patients, analyzing whether the addition of surgery improves survival when compared with definitive CT-RT alone. METHODS: From 1996 to 2006, 72 N2 NSCLC patients were treated. Thirty-four patients received cisplatin-based induction chemotherapy, followed by paclitaxel-cisplatin CT-RT, and 38 patients underwent surgery preceded by induction and/or followed by adjuvant therapy. Survival curves were estimated by Kaplan-Meier analysis, and the differences were assessed with the log-rank test. RESULTS: Most of the patients (87 %) were men. The median age was 59 years. A statistically significant association between T3-T4c and definitive CT-RT as well as between T1-T2c and surgery was noted (p < 0.0001). After a median follow-up period of 35 months, the median overall survival (OS) was 42 months for the surgery group versus 41 months for the CT-RT patients (p = 0.590). The median progression-free survival (PFS) was 14 months after surgery and 25 months after CT-RT (p = 0.933). Responders to radical CT-RT had a better OS than non-responders (43 vs. 17 months, respectively, p = 0.011). No significant differences were found in the OS or PFS between the pN0 [14 (37.8 %) patients] and non-pN0 patients at thoracotomy. Three treatment-related deaths (7.8 %) were observed in the surgical cohort and none in the CT-RT group. CONCLUSIONS: The addition of surgery did not render a median OS or PFS benefit when compared with CT-RT alone in our series of stage III-N2 NSCLC patients, in accordance with previously published data. However, responses to CT-RT had a greater impact in terms of OS and PFS. Although the patients selected for management including surgery showed a favorable T clinical staging in comparison to patients exclusively treated with definitive CT-RT, similar survival outcomes were found.

Treatment recommendations for metastatic colorectal cancer.

Metastatic colorectal cancer (CRC) represents an important health problem in which several biological predictive and prognostic factors have been identified, including clinical features and molecular markers that might influence the response to treatment. Actually, certain prognostic factors are considered key elements, along with disease extent, for deciding the therapeutic approach. However, a distinction between resectable/potentially resectable and unresectable patients must be made in order to establish an adequate therapeutic strategy. Different drugs and chemotherapy regimens are currently available, and their administration depends on patient characteristics, disease-related factors and the treatment objective. Moreover, special situations such as peritoneal carcinomatosis and local treatment of CRC in the setting of metastatic disease should be considered when deciding the most appropriate treatment strategy. This article reviews all the previously mentioned issues involved in the management of metastatic CRC and suggests some general recommendations for its treatment.

A new mutation in the hMSH2 gene in a Spanish Lynch syndrome family.

We report a new germline mutation in exon 13 of the hMSH2 gene (c.2081T>C; F694S) in a patient diagnosed with colorectal carcinoma. The patient's family fulfilled the clinical criteria of the Bethesda guidelines for Lynch syndrome. The segregation analysis determined the presence of the mutation in the proband's mother (breast cancer younger than 40 years old) and in two healthy daughters. The mutation was not present in 116 normal controls screened. The medical implications for the carrier relatives are discussed.

Progress in metastatic colorectal cancer: growing role of cetuximab to optimize clinical outcome.

The prognosis of metastatic colorectal cancer remains poor despite advances made in recent years, particularly with new treatments directed towards molecular targets. Cetuximab, a chimeric immunoglobulin (Ig)G1 monoclonal antibody that targets the ligand-binding domain of the epidermal growth factor receptor (EGFR), is active in metastatic colorectal cancer. As an IgG1 antibody, cetuximab may exert its antitumour efficacy through both EGFR antagonism and antibody-dependent cell-mediated cytotoxicity. The benefits of cetuximab in metastatic colorectal cancer are well documented in clinical trials and are acknowledged in the approval and licensing of this agent. There is evidence of the role of cetuximab not only in irinotecan-refractory or heavily pretreated patients, but also of the efficacy and safety of the addition of this agent to FOLFIRI (irinotecan/5-fluorouracil/leucovorin) in first-line metastatic colorectal cancer, with an enhanced effect in 5-fluorouracil patients with Kirsten rat sarcoma (KRAS) wild-type tumours. In these patients, a recent meta-analysis of the pooled Cetuximab Combined with Irinotecan in First-Line Therapy for Metastatic Colorectal Cancer (CRYSTAL) and Oxaliplatin and Cetuximab in First-Line Treatment of mCRC (OPUS) patient populations confirms that the addition of cetuximab to first-line chemotherapy achieves a statistically significant improvement in the best overall response, overall survival time, and progression-free survival (PSF) compared with chemotherapy alone. In nonresectable colorectal liver metastases, cetuximab plus FOLFOX-6 (oxaliplatin/5-fluorouracil/leucovorin) or cetuximab plus FOLFIRI increased significantly resectability of liver metastases, including R0 resections. Also, preliminary data indicate that cetuximab can be administered in a more convenient 2-week schedule in combination with standard chemotherapy. Cetuximab is generally well tolerated. Acne-form rash is the most frequent toxicity. Up to the present time, the results obtained with targeted therapy combinations are not as encouraging as initially expected. The identification of biomarkers associated with disease control, including KRAS and BRAF mutation status in patients treated with cetuximab, is changing the current management of metastatic colorectal cancer. Clinical and molecular predictive markers of response are under active evaluation in order to better select patients who could benefit from cetuximab treatment, with the aim of both optimising patient outcomes and avoiding unnecessary toxicities.

Selection of extreme phenotypes: the role of clinical observation in translational research.

Systematic collection of phenotypes and their correlation with molecular data has been proposed as a useful method to advance in the study of disease. Although some databases for animal species are being developed, progress in humans is slow, probably due to the multifactorial origin of many human diseases and to the intricacy of accurately classifying phenotypes, among other factors. An alternative approach has been to identify and to study individuals or families with very characteristic, clinically relevant phenotypes. This strategy has shown increased efficiency to identify the molecular features underlying such phenotypes. While on most occasions the subjects selected for these studies presented harmful phenotypes, a few studies have been performed in individuals with very favourable phenotypes. The consistent results achieved suggest that it seems logical to further develop this strategy as a methodology to study human disease, including cancer. The identification and the study with high-throughput techniques of individuals showing a markedly decreased risk of developing cancer or of cancer patients presenting either an unusually favourable prognosis or striking responses following a specific treatment, might be promising ways to maximize the yield of this approach and to reveal the molecular causes that explain those phenotypes and thus highlight useful therapeutic targets. This manuscript reviews the current status of selection of extreme phenotypes in cancer research and provides directions for future development of this methodology.

Factores ligados a angiogénesis, coagulación y fibrinólisis en el pronóstico de pacientes con cáncer colorrectal / Clotting, fibrinolysis and angiogénesis linked factors in the prognosis of colorectal carcinoma patients

Las plaquetas implicadas en la angiogénesis tumoral secretan factor de crecimiento endotelial vascular (VEGF). Los niveles de inhibidor del activador de plasminógeno tipo 1 (PAI-1) podrían regular la degradación de la matriz extracelular durante la angiogénesis. Durante este proceso tiene lugar la activación del sistema de la coagulación-fibrinólisis, que representa un evento clínico desfavorable. El factor de Von Willebrand (vWf), el dímero D (DD) y el fibrinógeno son marcadores sensibles de estos procesos. El recuento de plaquetas y los niveles de VEGF, PAI-1, vWf, DD y fibrinógeno podrían predecir la evolución clínica en pacientes con cáncer. En este estudio correlacionamos los niveles de VEGF, PAI-1, vWf, DD y fibrinógeno en pacientes con carcinoma colorrectal (CCR) en estadios I a IV sometidos a cirugía, a quimioterapia o a ambos métodos, con el análisis patológico/inmunohistoquímico en pacientes en estadios I-III y con la respuesta al tratamiento, y el riesgo de muerte en pacientes en estadio IV. Treinta y dos pacientes con CCR localizado o localmente avanzado y 32 con CCR metastático fueron evaluados. Las muestras sanguíneas se extrajeron antes de la cirugía y antes y después de la quimioterapia basada en fluoropirimidinas. Los enfermos en estadio IV recibieron una mediana de 3 ciclos de quimioterapia, entre muestras. En los pacientes en estadio I a III, los niveles basales de VEGF, recuento de plaquetas, fibrinógeno y PAI-1 se correlacionaron con el estadio tumoral. Además, la expresión tumoral de p21 y c-myc se asoció con niveles más elevados de vWf e inferiores de DD, respectivamente. En tumores metastásicos, los niveles prequimioterapia y posquimioterapia de VEGF, PAI-1 y CA19.9 se encontraron relacionados con las tasas de progresión.

Proteomic analysis in cancer research: potential application in clinical use.

The ultimate goal of cancer proteomics is to adapt proteomic technologies for routine use in clinical laboratories for the purpose of diagnostic and prognostic classification of disease states, as well as in evaluating drug toxicity and efficacy. The novel technologies allows researchers to facilitate the comprehensive analyses of genomes, transcriptomes, and proteomes in health and disease. The information that is expected from such technologies may soon exert a dramatic change in cancer research and impact dramatically on the care of cancer patients. Analysis of tumor-specific proteomic profiles may also allow better understanding of tumor development and the identification of novel targets for cancer therapy. The localization of gene products, which is often difficult to deduce from the sequence, can be determined experimentally. Mechanisms, such as regulation of protein function by proteolysis, recycling, and isolation in cell compartments, affect gene products, not genes. Finally, protein-protein interactions and the molecular composition of cellular structures can be determined only at the protein level. The biological variability among patient samples as well as the great dynamic range of biomarker concentrations are currently the main challenges facing efforts to deduce diagnostic patterns that are unique to specific disease states. While several strategies exist to address this problem, we have tried to offer a wide perspective about the current possibilities.

A panel discussion of controversies and challenges in the adjuvant treatment of colon cancer.

Current issues of adjuvant therapy for colon cancer concern the introduction of drugs other than fluorouracil-5/leucovorin (5-FU/LV), the benefits for stage II patients, the use of new primary endpoints and the influence of age on treatment benefits. These issues were addressed in a panel discussion and the conclusions were the following: FOLFOX4 is the first regimen that shows superiority over 5-FU/LV. The use of 3-year disease-free survival as primary endpoint could encourage the quicker adoption of improved therapeutic strategies into clinical practice. Available data suggest that there are some benefits for stage II patients, and the decision needs to be individualised for each patient. Further, therapeutic decisions based solely on the patient's age are inappropriate, and geriatric assessment tools will help in making this decision. This information would improve patient and physician understanding of the recent data regarding the potential benefits of adjuvant therapy.

[Dyspnea, oliguria and lower extremities edema in a patient undergoing mediastinic radiotherapy for a non-resectable thymic carcinoma]. / Disnea, oliguria y edema en extremidades inferiores en paciente en tratamiento de radioterapia mediastínica por carcinoma tímico irresecable.

In this case report we present the clinical signs and symptoms of cardiac tamponade of tumor origin. We explain the clinical investigations for its diagnosis as well as its specific differential diagnosis in cancer patients. The different therapeutic options are also presented together with a brief summary of the thymic carcinoma.