Sunday, 21 October 2018

Oligometastatic disease

The oligometastatic disease is an intermediate state between locally advanced and disseminated or multimetastatic cancer [1]. It has been based on the number of detectable metastatic lesions in imaging exams, with the threshold varying between 3 and 10 lesions. Singh et al. [2] reported that a number of metastases limited to five lesions developed during follow-up after curative treatment of primary tumor was significantly associated to better 5-year survival (73% vs. 43% of patients with more than five metastases). Therefore, patients with oligometastatic disease are thought to have improved outcomes compared with those with multimetastatic cancer, with greater median survivals [3]. Until there is genomic or proteomic data that provide a biological component for the definition of oligometastatic disease, a clinical diagnosis based on up to 5 extra-pelvic lesions is reasonable [4]. Relapse may be local or distant. The molecular basis of oliometastases is that they can act like primary tumours and are able to seed and form new metastases [5].
Bibliographic references:
[1] Hellman S, Weichselbaum RR. Oligometastases. J Clin Oncol. 1995 Jan;13(1):8-10. Available at: https://doi.org/10.1200/JCO.1995.13.1.8.
[2] Singh D, Yi WS, Brasacchio RA, Muhs AG, Smudzin T, Williams JP, et al. Is there a favorable subset of patients with prostate cancer who develop oligometastases? Int J Radiat Oncol Biol Phys. 2004 Jan 1;58(1):3-10. Available at: https://doi.org/10.1016/S0360-3016(03)01442-1.
[3] Tree AC, Khoo VS, Eeles RA, Ahmed M, Dearnaley DP, Hawkins MA, et al. Stereotactic body radiotherapy for oligometastases. Lancet Oncol. 2013 Jan;14(1):e28-37. Available at: https://doi.org/10.1016/S1470-2045(12)70510-7.
[4] Tosoian JJ, Gorin MA, Ross AE, Pienta KJ, Tran PT, Schaeffer EM. Oligometastatic prostate cancer: definitions, clinical outcomes, and treatment considerations. Nat Rev Urol. 2017 Jan;14(1):15-25. Available at: https://doi.org/10.1038/nrurol.2016.175.
[5] Gundem G, Van Loo P, Kremeyer B, Alexandrov LB, Tubio JMC, Papaemmanuil E, et al. The evolutionary history of lethal metastatic prostate cancer. Nature. 2015 Apr 16;520(7547):353-357. Available at: https://doi.org/10.1038/nature14347.

Oligoprogressive

The oligoprogressive phase is a relapsed phase of oligometastatic cancer after a cytoreductive treatment [1]. It «refers to disease progression at a limited number of anatomic sites, with continued response or stable disease at other sites of disease [2].» It can also be related «to patients with stage IV disease who are receiving active systemic therapy that is controlling most of the disease in the body but a small number of sites show disease progression [2].» «Oligoprogression refers to the clinical scenario where a few metastases progress, whereas all other metastases are stable or responding to a systemic therapy strategy. Unlike the oligometastatic state, there can be diffuse metastatic disease, therefore there is no upper limit about how many metastases a patient has. The key point is that with the exception of a few growing tumours, the majority of other tumours are not progressing [3].»
Bibliographic references:
[1] Alongi F, Mazzola R, Figlia V, Guckenberger M. Stereotactic body radiotherapy for lung oligometastases: Literature review according to PICO criteria. Tumori. 2018 Jun;104(3):148-156. Available at:https://doi.org/10.1177/0300891618766820.
[2] Kim C, Hoang CD, Kesarwala AH, et al. Role of Local Ablative Therapy in Patients with Oligometastatic and Oligoprogressive Non-Small Cell Lung Cancer. J Thorac Oncol. 2017 Feb;12(2):179-193. Available at: https://doi.org/10.1016/j.jtho.2016.10.012.
[3] Cheung P. Stereotactic body radiotherapy for oligoprogressive cancer. Br J Radiol. 2016 Oct;89(1066):20160251. Available at: https://doi.org/10.1259/bjr.20160251.

Oligorecurrent

The oligorecurrent phase is a relapsed phase of oligometastatic cancer [1]. «The conditions of oligorecurrence has a primary site of the cancer controlled, meaning that all gross recurrent or metastatic sites could be treated using local therapy [2].»
«Schema 1 shows one distant metastasis/recurrence with a primary lesion. Schema 2 shows two distant metastases/recurrences with a primary lesion.»
Source: [2].


«Schema 1 shows one distant metastasis/recurrence with a controlled primary lesion. Schema 2 shows two distant metastases/recurrences with a controlled primary lesion. The biggest difference between oligometastases and oligo-recurrences lies in the uncontrolled or controlled primary lesion. Oligo-recurrence requires a controlled primary lesion.»
Source: [2].

Bibliographic reference:
[1] Alongi F, Mazzola R, Figlia V, Guckenberger M. Stereotactic body radiotherapy for lung oligometastases: Literature review according to PICO criteria. Tumori. 2018 Jun;104(3):148-156. Available at: https://doi.org/10.1177/0300891618766820.
[2] Niibe Y, Hayakawa K. Oligometastases and oligo-recurrence: the new era of cancer therapy. Jpn J Clin Oncol. 2010 Feb;40(2):107-11. Available at: https://doi.org/10.1093/jjco/hyp167.

Thursday, 4 October 2018

Statistics

«The statistics studies how to collect data (How many? In what way?) and how to analyze them to obtain the information that allows answering the questions that we put. It is about producing knowledge through observation and analysis of reality, in an intelligent and objective way. It is the essence of the scientific method.»
«To summarize a set of information from a large dataset, certain quantities are selected which concentrate the most possible information, and through them - can be 5 or 6 points - we can get a fairly accurate idea of the behavior of the data in general. These amounts are normally divided into three groups: tendency (center), scale (or dispersion), and location.»
Bibliographic reference: Grima P. Os segredos da estatística - a certeza absoluta e outras ficções. National Geographic - Edição Especial Matemática. 2018:15.

Saturday, 18 August 2018

Basket study

Source: [4].

«Basket trials (or studies) test the effect of one drug on a single mutation in a variety of tumor types [baskets], at the same time. These studies also have the potential to greatly increase the number of patients who are eligible to receive certain drugs relative to other trials designs [1], «allowing researchers to analyze each cancer type individually, as well as assess the impact of the drug or drug combinations as a whole. Using this approach, it is possible to combine what would have been multiple phase 2 trials into a single study [4]». «In the evaluation of targeted therapies, basket trials have emerged as an approach to test the hypothesis that targeted therapies may be effective independent of tumor histology, as long as the molecular target is present [2].» «Most basket trials typically aim to answer multiple questions simultaneously [3].»

Bibliographic references:
[1] Clinical Trial Design and Methodology. ASCO. https://www.asco.org/research-progress/clinical-trials/clinical-trial-resources/clinical-trial-design-and-methodology. Accessed August 18, 2018.
[2] Redig AJ, Jänne PA. Basket trials and the evolution of clinical trial design in an era of genomic medicine. J Clin Oncol. 2015 Mar 20;33(9):975-7. Available at: https://doi.org/10.1200/JCO.2014.59.8433.
[3] Cunanan KM, Gonen M, Shen R, et al. Basket Trials in Oncology: A Trade-Off Between Complexity and Efficiency. J Clin Oncol. 2017 Jan 20;35(3):271-273. Available at: https://doi.org/10.1200/JCO.2016.69.9751.
[4] Illuminating ideas: Innovative clinical trial design. Roche.com. https://www.roche.com/research_and_development/who_we_are_how_we_work/clinical_trials/innovative-clinical-trial-design.htm. Accessed August 18, 2018.

Heart radiation


Source: Kim M. Radiating The Heart Saves Patty Sweeney. ABC30 Fresno. https://abc30.com/health/radiating-the-heart-saves-patty-sweeney/3966266/. Published 2018. Accessed August 18, 2018.

Wednesday, 15 August 2018

Febrile neutropaenia

«Febrile neutropaenia is defined as an oral temperature of >38.3°C or two consecutive readings of >38.0°C for 2 h and an absolute neutrophil count of <0.5 × 109/L, or expected to fall below 0.5 × 109/L.»
Bibliographic reference: Klastersky J, de Naurois J, Rolston K, Rapoport B, Maschmeyer G, Aapro M, Herrstedt J, on behalf of the ESMO Guidelines Committee; Management of febrile neutropaenia: ESMO Clinical Practice GuidelinesAnnals of Oncology, Volume 27, Issue suppl_5, 1 September 2016, Pages v111–v118, https://doi.org/10.1093/annonc/mdw325.

Monday, 13 August 2018

Multi-arm multi-stage (MAMS) trial design

Advanced/metastatic NSCLC treatment algorithm

Advanced/metastatic NSCLC [non-small cell lung cancer] treatment algorithm:
ALK: anaplastic lymphoma kinase; EGFR: epidermal growth factor receptor; PD-L1: programmed cell death ligand 1; ROS1: proto-oncogene receptor tyrosine-protein kinase; TPS: tumor proportion score.
Source: Brahmer JR, Govindan R, Anders RA, et al. The Society for Immunotherapy of Cancer consensus statement on immunotherapy for the treatment of non-small cell lung cancer (NSCLC). J Immunother Cancer. 2018 Jul 17;6(1):75. Available at: https://doi.org/10.1186/s40425-018-0382-2. Creative Commons license: https://creativecommons.org/publicdomain/zero/1.0/.


[French]


Sunday, 12 August 2018

Saturday, 28 July 2018

VMA (vanillylmandelic acid or DL-4-hydroxy-3-methoxymandelic acid)

It «is a chemical intermediate in the synthesis of artificial vanilla flavorings [1] and is an end-stage metabolite of the catecholamines, epinephrine, and norepinephrine. (...). VMA is found in the urine, along with other catecholamine metabolites, including homovanillic acid (HVA), metanephrine, and normetanephrine. In timed urine tests, the quantity excreted (usually per 24 hours) is assessed along with creatinine clearance, and the quantity of cortisols, catecholamines, and metanephrines excreted is also measured. Urinary VMA is elevated in patients with tumors that secrete catecholamines [2]. These urinalysis tests are used to diagnose an adrenal gland tumor called pheochromocytoma, (...). These tests may also be used to diagnose neuroblastomas [or other neuroendocrine tumors (e.g., ganglioblastoma, ganglioneuroma)], and to monitor treatment of these conditions [3].» Catecholamines «are released into the blood during times of physical or emotional stress, which are factors that may skew the results of the test [3].»
«The reference ranges of VMA in children are as follows [Burris, 2006, McPherson, 2011, and Wallach, 2011, cited by 4]:
  • Younger than 1 year: <27 mg/g creatinine;
  • Age 1-2 years: <18 mg/g creatinine;
  • Age 2-4 years: <13 mg/g creatinine;
  • Age 5-9 years: <8.5 mg/g creatinine;
  • Age 10-14 years: <7 mg/g creatinine.
The reference range in persons aged 15 years and older is 2-7 mg/24 hours [4].»
«In the evaluation of pheochromocytoma, vanillylmandelic acid is now considered the least-specific test for catecholamine metabolites, with a false-positive rate greater than 15%. Measurement of metanephrine, an intermediate metabolite between epinephrine and vanillylmandelic acid, is now considered the most sensitive and specific test for pheochromocytoma [4].»
Chemical formula: C9H10O5.
Bibliographic references:
[1] Fatiadi A, Schaffer R. An Improved Procedure for Synthesis of DL-4-Hydroxy-3-methoxymandelic Acid (DL-"Vanillyl"-mandelic Acid, VMA). Journal of Research of the National Bureau of Standards - A. Physics and Chemistry. 1974;78A(3):411–412. Available at: https://doi.org/10.6028/jres.078A.024.
[2] Magera MJ, Thompson AL, Matern D, Rinaldo P. Liquid chromatography-tandem mass spectrometry method for the determination of vanillylmandelic acid in urine. Clin Chem. 2003 May;49(5):825-6. Available at: https://doi.org/10.1373/49.5.825.
[3] Vanillylmandelic acid. En.wikipedia.org. https://en.wikipedia.org/wiki/Vanillylmandelic_acid. Published 2018. Accessed July 28, 2018.
[4] Lee A, Van Durme DJ. Vanillylmandelic Acid (VMA): Reference Range, Interpretation, Collection and Panels. Emedicine.medscape.com. https://emedicine.medscape.com/article/2089620-overview#a1. Published 2014. Accessed July 28, 2018.

Gaseous myelography or pneumomyelography

«Myelography developed as an imaging technique to assess the status of the thecal sac, spinal cord, and nerve roots in diverse pathologic conditions. Before the development of myelography, the only definitive means of evaluating these structures was laminectomy and direct inspection [1].»
«Myelographic techniques have evolved over time. The requirement for dural puncture, although invasive, offered the opportunity to acquire cerebrospinal fluid (CSF) specimens for laboratory analysis as a part of the procedure. (...). After spinal puncture, a myelographic contrast agent was slowly injected into the subarachnoid space with fluoroscopic confirmation. (...). Myelography is an invasive procedure, requiring puncture of the subarachnoid space. The spinal puncture is generally done below the L1-2 disc space level. Subarachnoid puncture also can be performed in the cervical spine at the C1-2 level via a lateral approach, or at the craniocervical junction via a posterior midline approach. (...). Although myelography has become a relatively safe test, it is invasive. MR imaging of the spine with its improved soft tissue delineation and excellent ability to depict and characterize extradural, intradural, and intramedullary lesions has led to a significant decrease in the use of myelography [1].»
«Several contrast agents have been used for myelography»: air and other gases, Thorotrast® (a suspension containing particles of the radioactive compound thorium dioxide), Lipiodol (ethiodized oil), Abrodil (sodium iodomethane sulfonate), Conray (iothalamate meglumine), Pantopaque (iophendylate), Dimer-X (methylglucamine iocarmate), metrixamide, iohexol and other nonionics [1].
«In 1919, Dr. Walter Dandy [2] suggested that the intraspinal air that was used for pneumoencephalography could be also used for the diagnosis of intraspinal pathology. A few years later, Dandy [1922, cited by 1] reported his experience with pneumomyelography in the diagnosis of spinal cord tumors. Attractive features of gas, specifically air, as a contrast medium include low cost, lack of allergic reactions, and spontaneous reabsorption. Other gases, such as oxygen, were also used for pneumomyelography because of their greater diffusibility and more prompt resorption. Gas is a negative contrast agent, and the optical contrast provided by plain radiography or tomography was poor. Although not chemically toxic, a variety of unpleasant side effects, such as headache, nausea, and transient neurologic symptoms, were common with air myelography. (...). The other disadvantage of pneumomyelography was that fluoroscopic images could not be used; rather, radiographs were obtained using overpenetrated technique. Even with the best technique, these studies were extremely challenging to perform and interpret [1].» «Advancements in contrast media development have led to significant improvement in their safety profile [1].» «The development of water-soluble contrast media allowed the use of post-myelographic computed tomography, which was a major advance [1].»
«Although myelography has largely been supplanted by MRI [magnetic resonance imaging], it will continue to be a necessary tool and is most useful in evaluation of cerebrospinal fluid leaks and in patients unable to undergo MRI [1].»
Bibliographic references:
[1] Price DB, Ortiz AO. Myelography: From Lipid-Based to Gadolinium-Based Contrast Agents. Magn Reson Imaging Clin N Am. 2017 Nov;25(4):713-724. Available at: https://doi.org/10.1016/j.mric.2017.06.005.
[2] Dandy WE. Roentgenography of the brain after the injection of air into the spinal canal. Ann Surg1919 Oct;70(4):397–403. Available at: https://doi.org/10.1097/00000658-191910000-00004.

Friday, 27 July 2018

Complete remission

«The disappearance of all signs of cancer in response to treatment. This does not always mean the cancer has been cured. Also called complete response [1].» «Complete remission can also be described by some doctors as no evidence of disease (NED) [2]». «Remission may also refer to the disease-free period. Although remission is a word that can be used in relation to any cancer, it is most associated with leukemia and Hodgkin's disease and the other lymphomas [3].» «Remission is almost always the result of some form of cancer treatment, such as radiation or chemotherapy [not surgery], although there are documented cases in which cancer goes into remission on its own [4].»
Bibliographic references:
[1] NCI Dictionary of Cancer Terms. National Cancer Institute. https://www.cancer.gov/publications/dictionaries/cancer-terms/def/complete-remission. Accessed July 27, 2018.
[2] What Is Cancer Remission?. Mesothelioma + Asbestos Awareness Center. https://www.maacenter.org/blog/what-is-cancer-remission/. Accessed July 27, 2018.
[3] Sarg M, Gross A. The Cancer Dictionary. 3rd ed. New York: Facts on Fire; 2007:268.
[4] Cancer Remission Definition - Southeast Radiation Oncology Group, P.A. - SERO - Treat Cancer. Southeast Radiation Oncology Group, P.A. - SERO - Treat Cancer. https://treatcancer.com/blog/cancer-remission-definition/. Accessed July 27, 2018.

Sunday, 22 July 2018

Molecular fingerprint

«Molecular fingerprints are a way of encoding the structure of a molecule. The most common type of fingerprint is a series of binary digits (bits) that represent the presence or absence of particular substructures in the molecule. Comparing fingerprints allows you to determine the similarity between two molecules, to find matches to a query substructure, etc. [1]». «Fingerprints are a very abstract representation of certain structural features of a molecule [2]». «The similarity-based virtual screening (a kind of ligand-based virtual screening) assumes that all compounds in a database that are similar to a query compound have similar biological activity. (...). To achieve high efficacy of similarity-based screening of databases containing millions of compounds, molecular structures are usually represented by molecular screens (structural keys) or by fixed-size or variable-size molecular fingerprints. Molecular screens and fingerprints can contain both 2D- and 3D-information [3]». «Molecular fingerprints encode properties of small molecules and assess their similarities computationally through bit string comparisons. Based on the similarity to a biologically active template, molecular fingerprint methods allow for identifying additional compounds with a higher chance of displaying similar biological activities against the same target – a process commonly referred to as virtual screening [4]». It is «a unique pattern indicating the presence of a particular molecule, based on specialized analytic techniques such as mass- or x-ray-spectroscopy, used to identify a pollutant, drug, contaminant, or other chemical in a test sample [5].»
Example [6]:
 Bibliographic references:
[1] 1. Molecular fingerprints and similarity searching — Open Babel v2.3.1 documentation. Openbabel.org. https://openbabel.org/docs/dev/Fingerprints/intro.html. Published 2011. Accessed July 22, 2018.
[2] 2. Daylight Theory: Fingerprints. Daylight.com. http://www.daylight.com/dayhtml/doc/theory/theory.finger.html. Published 2007. Accessed July 22, 2018.
[3] Chemical similarity. En.wikipedia.org. https://en.wikipedia.org/wiki/Chemical_similarity. Published 2018. Accessed July 22, 2018.
[4] Muegge I, Mukherjee P. An overview of molecular fingerprint similarity search in virtual screening. Expert Opin Drug Discov. 2016;11(2):137-48. Available at: https://doi.org/10.1517/17460441.2016.1117070.
[5] Chemical fingerprint dictionary definition | chemical fingerprint defined. Yourdictionary.com. http://www.yourdictionary.com/chemical-fingerprint. Published 2018. Accessed July 22, 2018.

[6] Luo W, Chan KC. Discovering patterns in drug-protein interactions based on their fingerprints. BMC Bioinformatics. 2012 Jun 11;13 Suppl 9:S4. Available at: https://doi.org/10.1186/1471-2105-13-S9-S4.

Sunday, 15 July 2018

Failed randomized clinical trials in Radiation Oncology: what can we learn?

Failed randomized clinical trials in Radiation Oncology: what can we learn?: Randomized clinical trials are essential to evidence-based medicine, yet a significant proportion fail to be completed. In Radiation Oncology, factors contributing to trial failure are not well understood. We sought to compare completed and incomplete clinical trials involving radiation therapy to identify predictors of trial failure.

Wednesday, 11 July 2018

Gorlin syndrome, nevoid basal cell carcinoma syndrome, or Gorlin-Goltz syndrome

It «is a condition that affects many areas of the body and increases the risk of developing various cancerous and noncancerous tumors. (...). Individuals with Gorlin syndrome typically begin to develop basal cell carcinomas during adolescence or early adulthood. (...). Some people with Gorlin syndrome never develop any basal cell carcinomas, while others may develop thousands of these cancers. (...). Most people with Gorlin syndrome also develop noncancerous (benign) tumors of the jaw, called keratocystic odontogenic tumors (...). Individuals with Gorlin syndrome have a higher risk than the general population of developing other tumors. A small proportion of affected individuals develop a brain tumor called medulloblastoma during childhood. A type of benign tumor called a fibroma can occur in the heart or in a woman's ovaries (...). Other features of Gorlin syndrome include small depressions (pits) in the skin of the palms of the hands and soles of the feet; an unusually large head size (macrocephaly) with a prominent forehead; and skeletal abnormalities involving the spine, ribs, or skull [1].» «Ectopic calcification, particularly in the falx, is present in more than 90% of affected individuals by age 20 years [2].»
Mutations in the PTCH1 (protein patched homolog 1) gene cause Gorlin syndrome [1,3]. This protein «is the receptor for sonic hedgehog, a secreted molecule implicated in the formation of embryonic structures and in tumorigenesis. This gene functions as a tumor suppressor. The PTCH1 gene product is a transmembrane protein that suppresses the release of another protein called smoothened, and when sonic hedgehog binds PTCH1, smoothened is released and signals cell proliferation [3].» «The characteristic features of Gorlin syndrome can also be associated with a chromosomal change called a 9q22.3 microdeletion, in which a small piece of chromosome 9 is deleted in each cell. This deletion includes the segment of chromosome 9 that contains the PTCH1 gene [1].
«Gorlin syndrome is inherited in an autosomal dominant pattern [1].»
«Life expectancy (...) is not significantly different from average [2].»
These patients have a relative contraindication for radiotherapy [4].
Bibliographic reference:
[1] Gorlin syndrome. Genetics Home Reference. https://ghr.nlm.nih.gov/condition/gorlin-syndrome#genes. Published 2018. Accessed July 11, 2018.
[2] Evans DG, Farndon PA. Gorlin syndrome - Conditions - GTR - NCBI. Ncbi.nlm.nih.gov. https://www.ncbi.nlm.nih.gov/gtr/conditions/C0004779/. Accessed July 11, 2018.
[3] PTCH1. En.wikipedia.org. https://en.wikipedia.org/wiki/PTCH1. Published 2017. Accessed July 11, 2018.
[4] Singer L, Yom SS. Chapter 1 - Skin Cancer. In: Hansen EK, Roach III M. Handbook Of Evidence-Based Radiation Oncology. 3rd ed. Cham, Switzerland: Springer; 2018:10. Available at: https://doi.org/10.1007/978-3-319-62642-0.

Wednesday, 20 June 2018

Comparison of local recurrence among early breast cancer patients treated with electron intraoperative radiotherapy vs hypofractionated photon radiotherapy: an observational study

Comparison of local recurrence among early breast cancer patients treated with electron intraoperative radiotherapy vs hypofractionated photon radiotherapy: an observational study: PURPOSE: To evaluate local recurrence (LR) in women with early breast cancer (BC) who underwent intraoperative radiation therapy with electrons particles (IORT-E) or adjuvant hypofractionated external radiotherapy (HYPOFX). MATERIALS AND METHODS:We retrospectively analyzed 470 patients with early BC treated at our center from September 2009 to December 2012. 235 women were treated with breast-conserving surgery and immediate IORT-E (21 Gy/1 fraction) while 235 patients underwent wide excision followed by hypofractionated whole breast irradiation. Radiotherapy modality was chosen according an individualized decision based on tumour features, stage, technical feasibility, age, acceptance to be enrolled in the IORT-E group.RESULTS: After a median follow-up of 6 years, we observed 8 (3.4%) and 1 (0.42%) LR in the IORT-E and in the HYPOFX group (p=0.02), respectively. The two groups differed in the prevalence of clinical characteristics (p4 and 1 women in the IORT-E and HYPOFX group died for breast cancer, respectively (p=0.167). OS and DFS hazard ratio [HR] were 2.14 (95% IC, 1.10 to 4.15) and 2.09 (95% IC, 1.17 to 3.73), respectively. CONCLUSIONS:Our comparison showed that IORT-E and HYPOFX are two effective radiotherapy modalities after conservative surgery in early BC. However, at 6 years a significant higher rate of LR occurred in patients submitted to IORT-E with respect to HYPOFX. This finding may be correlated to some subsets of patients who, depending on the biological...

Tuesday, 19 June 2018

Radiotherapy utilization and fractionation patterns during the first course of cancer treatment in the United States from 2004 to 2014

Radiotherapy utilization and fractionation patterns during the first course of cancer treatment in the United States from 2004 to 2014: The changing use of radiation as a first-line cancer therapy in the United States is poorly characterized. This study aims to report radiotherapy utilization and fractionation patterns during the first course of cancer treatment.