Cancer chemotherapy failure: a synthetic view

Cancer is a highly prevalent and fatal disease, being one of the main causes of death in Brazil and in the world. In the last decades, a great advance has been reached in fight against cancer, with some translation in curability. However, these advances are still insufficient, and the prognosis of the cancer patient is usually unfavorable. Indeed, there are still many gaps in our knowledge about this complex and heterogeneous disease. Several treatments approaches against cancer are available to clinical practice - and some others are being developed - one of which is chemotherapy, both traditional and targeted therapy (TT), used - above all - as primary treatment for metastatic or secondary treatment in local or locally advanced disease. Several factors can act through many mechanisms to determine the failure of chemotherapy treatment. These factors are distributed across the various biological scales, from the molecular to the socioeconomic level, making the holistic view of treatment a great challenge and impairing the awareness of what can go wrong. The purpose of this paper is to be a comprehensive - but not superficial - picture of the many factors that influence the success of chemotherapy. In this way, the result of this work was this discussion on chemotherapy failure, were it was exposed recent advances, challenges to be overcome and new paths to be explored on this field.O Câncer é uma doença de alta prevalência e letalidade, sendo uma das principais causas de morte no Brasil e no mundo. Nas últimas décadas, grandes avanços foram alcançados na luta contra o câncer, com alguma tradução em curabilidade. Contudo, esses avanços ainda não são suficientes, de modo que o prognóstico do paciente com câncer ainda é, geralmente, desfavorável. De fato, há ainda diversas lacunas em nosso conhecimento a respeito dessa complexa e heterogênea doença. Diversos tratamentos contra o câncer já estão disponíveis à prática clínica - e outros ainda estão sendo desenvolvidos - uma delas a quimioterapia, tanto a tradicional quando a alvo dirigida, utilizada, sobretudo, como tratamento primário contra doença metastática ou secundário contra doença local ou localmente avançada. Diversos fatores podem atuar, através de vários mecanismos, de modo a determinar a falha do tratamento quimioterápico. Esses fatores estão distribuídos ao longo de diversas escalas biológicas, do nível molecular ao socioeconômico, tornando uma visão holística do tratamento um grande desafio, prejudicando a compreensão acerca do que pode dar errado. O objetivo deste trabalho é ser uma leitura compreensiva - mas não superficial - dos muitos fatores que influenciam o sucesso de quimioterapia. Deste modo, o resultado foi a presente discussão, na qual foram expostos avanços recentes, desafios a serem superados e novos caminhos a serem explorados na área

Effect of salivary gland cooling in 68Ga-PSMA uptake

Introduction: Techniques using PSMA radioligands have emerged as diagnostic and therapeutic alternatives in prostate cancer. Significant adverse events resulting from using beta-emitters such as 177Lu-PSMA for castration-resistant prostate cancer therapy include sialotoxicity and xerostomia. Sialotoxicity ranges from 8% mild to moderate up to 10% interruption of treatment, depending on the compound used, due to the physiological expression of PSMA in the salivary glands and consequent radioligand uptake. Cooling with icepacks emerged as a possible intervention to prevent this event. The rationale is that cold- induced vasoconstriction would lead to a reduction of the perfusion of the gland, similarly to scalp cooling applied in some chemotherapies. Although empirically used in European protocols, the efficacy of this technique was assessed in only one study, with no evidence of success. The objective of this work was to analyze the efficacy of salivary gland cooling in the reduction of PSMA radioligand uptake.Methodology: Unilateral cooling of the salivary glands was performed for 10 prostate cancer patients submitted to PET-CT with Ga68PSMA, a compound used for diagnostic purposes and validated mainly in biochemical recurrence scenario. For cooling, icepacks were coupled to a device that attached them to one of the patient's parotid gland. Cooling started 30 minutes before the injection of the radiopharmaceutical. The test was started 1h after the injection (acquisition t1), with an approximate duration of 30 minutes. A delayed image was made 4h after the injection (acquisition t4). The cooling was suspended just after the t1 acquisition. The packs were replaced every 30 minutes, and their temperature measured and recorded using infrared thermometers, for temperature standardization. Using OsiriX Dicom Viewer software, each of the glands (cooled parotid and control, cooled submandibular and control) was quantitatively assessed by the standardized maximum, mean and peak uptake values (SUVmax, SUVmean, and SUVpeak). The gland was delimited through an isocontour generated from a threshold of 10% of the SUVmax within a defined volume of interest (VOI). These four parameters were compared through the paired Student's T-test using R Commander software.Results: There was no statistically significant reduction in any of the SUV parameters in the cooled glands compared to contralateral controls, both in t1 in t4. Regarding the submandibular glands, there were also found no alterations of statistical relevance, but the means of the three SUV parameters were higher in the cooled glands that in the controls.Discussion: Results indicated no significant reduction of the radiation absorbed dose by cooled salivary glands. Despite the small sample size, that could reduce the ability to detect significant variations, results allow inferring that biological effects, if present, are probably small and of little clinical significance. Therefore, it was considered that results did not justify performing further exams since this is a high cost and complexity technique. The present findings corroborate with the other mentioned study.Conclusion: The cooling of the salivary glands does not significantly reduce their uptake of radiopharmaceuticals, and no evidence supports this technique for sialotoxicity and xerostomia prevention in clinical practice