Interventional oncology

Last updated

Interventional oncology (abbreviated IO) is a subspecialty field of interventional radiology that deals with the diagnosis and treatment of cancer and cancer-related problems using targeted minimally invasive procedures performed under image guidance. [1] [2] Interventional oncology has developed to a separate pillar of modern oncology and it employs X-ray, ultrasound, computed tomography (CT) or magnetic resonance imaging (MRI) to help guide miniaturized instruments (e.g. biopsy needles, ablation electrodes, intravascular catheters) to allow targeted and precise treatment of solid tumours (also known as neoplasms) located in various organs of the human body, including but not limited to the liver, kidneys, lungs, and bones. [3] [4] Interventional oncology treatments are routinely carried out by interventional radiologists in appropriate settings and facilities. [5]

Contents

Procedures performed

Interventional oncology procedures are generally divided between diagnostic procedures that help obtain tissue diagnosis of suspicious neoplasms and therapeutic ones that aim to cure or palliate the tumour. Therapeutic interventional oncology procedures may be classified further into ablation techniques that destroy neoplastic tissues by delivery of some form of heat, cryo or electromagnetic energy and embolization techniques that aim to occlude the blood vessels feeding the tumour and thereby destroy it by means of ischemia. Both ablation and embolization techniques are minimally invasive treatment, i.e. they may be delivered through the skin (in a percutaneous way) without the need for any skin incisions or other form of open surgery. Hence, most treatments are nowadays offered as day case or outpatient appointments and patients may enjoy rapid recovery and minimal pain and discomfort with low rates of complications. [6]

Diagnostic techniques

Image-guided tumor ablation

Uses different types of energy to burn (radiofrequency ablation (RFA) and microwave ablation (MWA)), deliver electrical fields/electroporate (irreversible electroporation(IRE)) or freeze (cryoablation) solid tumors resulting in tumor cell death. Ablation techniques can be performed throughout the body such as in the lung, [7] liver, [8] [9] kidney, [10] prostate, [11] breast, [12] bone, [13] and other organs using image guidance to place a needle/probe through the skin into the target tissue.

High-intensity focused ultrasound (HIFU)

Uses a machine that emits high frequency sound waves to kill cancer cells and provide relief for tumor-related pain, such as in the bone.

Embolisation therapies

Palliative treatments

Interventional oncology has long been used to provide palliative care for patients. IO procedures can help reduce cancer-related pain and improve patients’ quality of life. Tumours can intrude into various ducts and blood vessels of the body, obstructing the vital passage of food, blood or waste. The interventional radiological treatment known as stenting can be used to re-open blockages, for example of the esophagus or bile ducts in cases of esophageal cancer or cholangiocarcinoma, respectively, considerably relieving the patient's adverse symptoms. [22]

Diseases treated

Interventional oncology (IO) procedures are commonly applied to treat primary or metastatic cancer. IO treatments may be also offered in combination with any of the above oncological therapies in order to augment the therapeutic outcome in more complex or widespread (metastatic) cancer cases. There is a variety of applications of interventional oncological treatments for tumors that arise in the:

Milestones

Benefits

While the surgical resection of tumours is generally accepted to offer the best long-term solution, it is often not possible due to the size, number or location of the tumour. IR therapies may be applied to shrink the tumour, making a surgical or interventional treatment possible. Some patient groups may also be too weak to undergo open surgery. IR treatments can be applied in these complex cases to provide effective and milder forms of treatment. Interventional oncological techniques can also be used in combination with other treatments to help increase their efficacy. For example, IO techniques can be used to shrink large tumours making them easier to excise. Chemotherapeutic drugs can also be administered intra-arterially, increasing their potency and removing the harsh effects of system-wide application.

Patients can greatly benefit from IO treatments. The minimally invasive nature of the treatments means they cause less pain, fewer side effects and shorter recovery times. Many IO procedures can be performed on an outpatient basis, freeing up hospital beds and reducing costs. [33]

Further considerations

Multidisciplinary approach

Cancer is a multifaceted disease group that requires a multidisciplinary approach to treatment. Numerous studies have shown that cancer patients treated in multidisciplinary environments benefit greatly from the combined expertise. Interventional Radiologists are seen as playing a major role in multidisciplinary cancer teams where they provide innovative solutions to improve combined therapies and to treat complications. [34]

Patient selection

Proper patient selection is the key element for the success of any medical procedure and improper conduct can have fatal consequences. Patient selection protocols must be strictly followed before treating patients with IO procedures.

Radiation protection

IO treatments are carried out under image guidance. For this reason practitioners must have attained solid training in radiation protection.

See also

Related Research Articles

<span class="mw-page-title-main">Hepatocellular carcinoma</span> Medical condition

Hepatocellular carcinoma (HCC) is the most common type of primary liver cancer in adults and is currently the most common cause of death in people with cirrhosis. HCC is the third leading cause of cancer-related deaths worldwide.

<span class="mw-page-title-main">Bone tumor</span> Medical condition

A bone tumor is an abnormal growth of tissue in bone, traditionally classified as noncancerous (benign) or cancerous (malignant). Cancerous bone tumors usually originate from a cancer in another part of the body such as from lung, breast, thyroid, kidney and prostate. There may be a lump, pain, or neurological signs from pressure. A bone tumor might present with a pathologic fracture. Other symptoms may include fatigue, fever, weight loss, anemia and nausea. Sometimes there are no symptoms and the tumour is found when investigating another problem.

<span class="mw-page-title-main">Interventional radiology</span> Medical subspecialty

Interventional radiology (IR) is a medical specialty that performs various minimally-invasive procedures using medical imaging guidance, such as x-ray fluoroscopy, computed tomography, magnetic resonance imaging, or ultrasound. IR performs both diagnostic and therapeutic procedures through very small incisions or body orifices. Diagnostic IR procedures are those intended to help make a diagnosis or guide further medical treatment, and include image-guided biopsy of a tumor or injection of an imaging contrast agent into a hollow structure, such as a blood vessel or a duct. By contrast, therapeutic IR procedures provide direct treatment—they include catheter-based medicine delivery, medical device placement, and angioplasty of narrowed structures.

<span class="mw-page-title-main">Embolization</span> Passage and lodging of an embolus within the bloodstream

Embolization refers to the passage and lodging of an embolus within the bloodstream. It may be of natural origin (pathological), in which sense it is also called embolism, for example a pulmonary embolism; or it may be artificially induced (therapeutic), as a hemostatic treatment for bleeding or as a treatment for some types of cancer by deliberately blocking blood vessels to starve the tumor cells.

Transcatheter arterial chemoembolization (TACE) is a minimally invasive procedure performed in interventional radiology to restrict a tumor's blood supply. Small embolic particles coated with chemotherapeutic drugs are injected selectively through a catheter into an artery directly supplying the tumor. These particles both block the blood supply and induce cytotoxicity, attacking the tumor in several ways.

<span class="mw-page-title-main">Radiofrequency ablation</span> Surgical procedure

Radiofrequency ablation (RFA), also called fulguration, is a medical procedure in which part of the electrical conduction system of the heart, tumor or other dysfunctional tissue is ablated using the heat generated from medium frequency alternating current. RFA is generally conducted in the outpatient setting, using either local anesthetics or twilight anesthesia. When it is delivered via catheter, it is called radiofrequency catheter ablation.

<span class="mw-page-title-main">Cryoablation</span> Process using extreme cold to destroy tissue

Cryoablation is a process that uses extreme cold to destroy tissue. Cryoablation is performed using hollow needles (cryoprobes) through which cooled, thermally conductive, fluids are circulated. Cryoprobes are positioned adjacent to the target in such a way that the freezing process will destroy the diseased tissue. Once the probes are in place, the attached cryogenic freezing unit removes heat from ("cools") the tip of the probe and by extension from the surrounding tissues.

<span class="mw-page-title-main">Selective internal radiation therapy</span>

Selective internal radiation therapy (SIRT), also known as transarterial radioembolization (TARE), radioembolization or intra-arterial microbrachytherapy is a form of radionuclide therapy used in interventional radiology to treat cancer. It is generally for selected patients with surgically unresectable cancers, especially hepatocellular carcinoma or metastasis to the liver. The treatment involves injecting tiny microspheres of radioactive material into the arteries that supply the tumor, where the spheres lodge in the small vessels of the tumor. Because this treatment combines radiotherapy with embolization, it is also called radioembolization. The chemotherapeutic analogue is called chemoembolization, of which transcatheter arterial chemoembolization (TACE) is the usual form.

<span class="mw-page-title-main">Bone metastasis</span> Medical condition

Bone metastasis, or osseous metastatic disease, is a category of cancer metastases that result from primary tumor invasions into bones. Bone-originating primary tumors such as osteosarcoma, chondrosarcoma, and Ewing sarcoma are rare; the most common bone tumor is a metastasis. Bone metastases can be classified as osteolytic, osteoblastic, or both. Unlike hematologic malignancies which originate in the blood and form non-solid tumors, bone metastases generally arise from epithelial tumors and form a solid mass inside the bone. Bone metastases, especially in a state of advanced disease, can cause severe pain, characterized by a dull, constant ache with periodic spikes of incident pain.

Microwave ablation is a form of thermal ablation used in interventional radiology to treat cancer. MWA uses electromagnetic waves in the microwave energy spectrum to produce tissue-heating effects. The oscillation of polar molecules produces frictional heating, ultimately generating tissue necrosis within solid tumors. It is generally used for the treatment and/or palliation of solid tumors in patients who are nonsurgical candidate.

Irreversible electroporation is a soft tissue ablation technique using short but strong electrical fields to create permanent and hence lethal nanopores in the cell membrane, to disrupt cellular homeostasis. The resulting cell death results from induced apoptosis or necrosis induced by either membrane disruption or secondary breakdown of the membrane due to transmembrane transfer of electrolytes and adenosine triphosphate. The main use of IRE lies in tumor ablation in regions where precision and conservation of the extracellular matrix, blood flow and nerves are of importance. The first generation of IRE for clinical use, in the form of the NanoKnife System, became commercially available for research purposes in 2009, solely for the surgical ablation of soft tissue tumors. Cancerous tissue ablation via IRE appears to show significant cancer specific immunological responses which are currently being evaluated alone and in combination with cancer immunotherapy.

DFINE, Inc. was an American medical device company with headquarters in San Jose, California. It was known for its development of minimally invasive therapeutic devices built upon a radiofrequency platform for the treatment of spinal diseases. The platform included two applications, the StabiliT Vertebral Augmentation System for the treatment of vertebral compression fractures and the STAR Tumor Ablation System for pain relief treatment of metastatic spinal tumors.

Targeted radiofrequency ablation is a minimally invasive procedure to treat severe pain and discomfort caused from metastatic tumors in the vertebral body of the spine. This procedure uses radiofrequency energy to target and ablate a specific spinal tumor, causing it shrink and reduce the pressure on the surrounding nerves and tissues. The procedure minimizes damage to the vertebrae and surrounding tissues. It is used as a palliative therapy rather with the intention of treating the cancer itself.

Hepatic artery embolization, also known as trans-arterial embolization (TAE), is one of the several therapeutic methods to treat primary liver tumors or metastases to the liver. The embolization therapy can reduce the size of the tumor, and decrease the tumor's impact such its hormone production, effectively decreasing symptoms. The treatment was initially developed in the early 1970s. The several types of hepatic artery treatments are based on the observation that tumor cells get nearly all their nutrients from the hepatic artery, while the normal cells of the liver get about 70-80 percent of their nutrients and 50% their oxygen supply from the portal vein, and thus can survive with the hepatic artery effectively blocked. In practice, hepatic artery embolization occludes the blood flow to the tumors, achieving significant tumor shrinkage in over 80% of people. Shrinkage rates vary.

Cryoimmunotherapy, also referred to as cryoimmunology, is an oncological treatment for various cancers that combines cryoablation of tumor with immunotherapy treatment. In-vivo cryoablation of a tumor, alone, can induce an immunostimulatory, systemic anti-tumor response, resulting in a cancer vaccine—the abscopal effect. Thus, cryoablation of tumors is a way of achieving autologous, in-vivo tumor lysate vaccine and treat metastatic disease. However, cryoablation alone may produce an insufficient immune response, depending on various factors, such as high freeze rate. Combining cryotherapy with immunotherapy enhances the immunostimulating response and has synergistic effects for cancer treatment.

Portal vein embolization (PVE) is a preoperative procedure performed in interventional radiology to initiate hypertrophy of the anticipated future liver remnant a couple weeks prior to a major liver resection procedure. The procedure involves injecting the right or left portal vein with embolic material to occlude portal blood flow. By occluding the blood flow to areas of the liver that will be resected away, the blood is diverted to healthy parts of the liver and induces hyperplasia. This may allow for a more extensive resection or stage bilateral resections that would otherwise be contraindicated resulting in better oncological treatment outcomes.

Radiation lobectomy is a form of radiation therapy used in interventional radiology to treat liver cancer. It is performed in patients that would be surgical candidates for resection, but cannot undergo surgery due to insufficient remaining liver tissue. It consists of injecting small radioactive beads loaded with yttrium-90 into the hepatic artery feeding the hepatic lobe in which the tumor is located. This is done with the intent of inducing growth in the contralateral hepatic lobe, not dissimilarly from portal vein embolization (PVE).

Ultrasonography of liver tumors involves two stages: detection and characterization.

Transarterial bland embolization is a catheter-based tumor treatment of the liver. In this procedure, embolizing agents can be delivered through the tumor’s feeding artery in order to completely occlude the tumor’s blood supply. The anti-tumor effects are solely based on tumor ischemia and infarction of tumor tissue, as no chemotherapeutic agents are administered. The rationale for the use of bland embolization for hepatocellular carcinoma (HCC) and/or other hyper-vascular tumors is based on the fact that a normal liver receives a dual blood supply from the hepatic artery (25%) and the portal vein (75%). As the tumor grows, it becomes increasingly dependent on the hepatic artery for blood supply. Once a tumor nodule reaches a diameter of 2 cm or more, most of the blood supply is derived from the hepatic artery. Therefore, bland embolization and transarterial chemoembolization (TACE) consist of the selective angiographic occlusion of the tumor arterial blood supply with a variety of embolizing agents, with or without the precedence of local chemotherapy infusion. The occlusion by embolic particles results in tumor hypoxia and necrosis, without affecting the normal hepatic parenchyma.

Damian E. Dupuy, M.D., F.A.C.R. is an Adjunct Professor of Diagnostic Imaging at Brown University's Warren Alpert Medical School and Director of Ablation services at Cape Cod Hospital. He is also a Member of Cape Cod preferred Physicians.

References

  1. ↑ Hickey, Ryan; Vouche, Michael; Sze, Daniel Y.; Hohlastos, Elias; Collins, Jeremy; Schirmang, Todd; Memon, Khairuddin; Ryu, Robert K.; Sato, Kent; Chen, Richard; Gupta, Ramona; Resnick, Scott; Carr, James; Chrisman, Howard B.; Nemcek, Albert A.; Vogelzang, Robert L.; Lewandowski, Robert J.; Salem, Riad (2013). "Cancer Concepts and Principles: Primer for the Interventional Oncologist—Part II". Journal of Vascular and Interventional Radiology. 24 (8): 1167–1188. doi:10.1016/j.jvir.2013.04.023. PMC   3800031 . PMID   23810312.
  2. ↑ Hickey, Ryan; Vouche, Michael; Sze, Daniel Y.; Hohlastos, Elias; Collins, Jeremy; Schirmang, Todd; Memon, Khairuddin; Ryu, Robert K.; Sato, Kent; Chen, Richard; Gupta, Ramona; Resnick, Scott; Carr, James; Chrisman, Howard B.; Nemcek, Albert A.; Vogelzang, Robert L.; Lewandowski, Robert J.; Salem, Riad (2013). "Cancer Concepts and Principles: Primer for the Interventional Oncologist—Part I". Journal of Vascular and Interventional Radiology. 24 (8): 1157–1164. doi:10.1016/j.jvir.2013.04.024. PMC   3800037 . PMID   23809510.
  3. ↑ "Interventional Radiology Treatments for Liver Cancer". Archived from the original on 2016-12-04. Retrieved 2015-05-07.
  4. ↑ Pereira, Philippe L.; Salvatore, Masala; Cardiovascular Interventional Radiological Society of Europe (CIRSE) (2012). "Standards of Practice: Guidelines for Thermal Ablation of Primary and Secondary Lung Tumors". CardioVascular and Interventional Radiology. 35 (2): 247–254. doi: 10.1007/s00270-012-0340-1 . PMID   22271076. S2CID   20280474.
  5. ↑ The Royal College of Radiologists UK. Interventional Oncology: Guidance for Service delivery
  6. ↑ Cardiovascular and Interventional Radiological Society of Europe, "IR Procedures"
  7. ↑ "Radiofrequency ablation for lung cancer". nhs.uk. 2017-08-21. Retrieved 2019-10-29.
  8. ↑ Radiology (ACR), Radiological Society of North America (RSNA) and American College of. "Radiofrequency Ablation (RFA) | Microwave Ablation (MWA) - Liver Tumors". www.radiologyinfo.org. Retrieved 2019-10-29.
  9. ↑ "Phase 3 Study of ThermoDox With Radiofrequency Ablation (RFA) in Treatment of Hepatocellular Carcinoma (HCC) - Full Text View - ClinicalTrials.gov". clinicaltrials.gov. 24 March 2017. Retrieved 2019-10-29.
  10. ↑ El Dib, Regina; Touma, Naji J.; Kapoor, Anil (August 2012). "Cryoablation vs radiofrequency ablation for the treatment of renal cell carcinoma: a meta-analysis of case series studies". BJU International. 110 (4): 510–516. doi: 10.1111/j.1464-410X.2011.10885.x . ISSN   1464-410X. PMID   22304329. S2CID   36726814.
  11. ↑ "Cryotherapy for Prostate Cancer". www.cancer.org. Retrieved 2019-10-29.
  12. ↑ Sabel, Michael S. (July 2014). "Nonsurgical ablation of breast cancer: future options for small breast tumors". Surgical Oncology Clinics of North America. 23 (3): 593–608. doi:10.1016/j.soc.2014.03.009. ISSN   1558-5042. PMID   24882353.
  13. ↑ Santiago, Fernando Ruiz; del Mar Castellano García, María; Montes, Jose Luis Martínez; García, Manuel Ruiz; Fernández, Juan Miguel Tristán (2009-01-07). "Treatment of bone tumours by radiofrequency thermal ablation". Current Reviews in Musculoskeletal Medicine. 2 (1): 43–50. doi:10.1007/s12178-008-9042-3. ISSN   1935-973X. PMC   2684952 . PMID   19468917.
  14. ↑ Napoli, Alessandro; Anzidei, Michele; Marincola, Beatrice Cavallo; Brachetti, Giulia; Noce, Vincenzo; Boni, Fabrizio; Bertaccini, Luca; Passariello, Roberto; Catalano, Carlo (2013). "MR Imaging–guided Focused Ultrasound for Treatment of Bone Metastasis". Radiographics. 33 (6): 1555–1568. doi:10.1148/rg.336125162. PMID   24108551.
  15. ↑ Gangi, A.; Basile, A.; Buy, X.; Alizadeh, H.; Sauer, B.; Bierry, G. (2005). "Radiofrequency and laser ablation of spinal lesions". Seminars in Ultrasound, CT and MRI. 26 (2): 89–97. doi:10.1053/j.sult.2005.02.005. PMID   15856810.
  16. ↑ Shah, Rajesh P.; Brown, Karen T.; Sofocleous, Constantinos T. (October 2011). "Arterially directed therapies for hepatocellular carcinoma". American Journal of Roentgenology. 197 (4): W590–602. doi:10.2214/AJR.11.7554. ISSN   1546-3141. PMID   21940531.
  17. 1 2 Salem, Riad; Lewandowski, Robert J. (June 2013). "Chemoembolization and radioembolization for hepatocellular carcinoma". Clinical Gastroenterology and Hepatology. 11 (6): 604–611. doi: 10.1016/j.cgh.2012.12.039 . ISSN   1542-7714. PMC   3800021 . PMID   23357493.
  18. ↑ "Chemotherapy Delivery Options: Benefits of Regional Therapies". Cancer Treatment Centers of America. 2018-10-17. Retrieved 2019-10-29.
  19. ↑ Al-Adra, D. P.; Gill, R. S.; Axford, S. J.; Shi, X.; Kneteman, N.; Liau, S.-S. (January 2015). "Treatment of unresectable intrahepatic cholangiocarcinoma with yttrium-90 radioembolization: a systematic review and pooled analysis". European Journal of Surgical Oncology. 41 (1): 120–127. doi:10.1016/j.ejso.2014.09.007. ISSN   1532-2157. PMC   4316196 . PMID   25449754.
  20. ↑ Cancer Treatment Center of America, Intra-Arterial chemotherapy
  21. ↑ May, Benjamin J.; Madoff, David C. (June 2012). "Portal vein embolization: rationale, technique, and current application". Seminars in Interventional Radiology. 29 (2): 81–89. doi:10.1055/s-0032-1312568. ISSN   0739-9529. PMC   3444878 . PMID   23729977.
  22. ↑ Katsanos, K.; Ahmad, F.; Dourado, R.; Sabharwal, T.; Adam, A. (2009). "Interventional radiology in the elderly". Clinical Interventions in Aging. 4: 1–15. PMC   2685220 . PMID   19503761.
  23. ↑ "Liver Cancer Interventional Radiology: Minimally Invasive". Cancer Treatment Centers of America. 2018-10-05. Retrieved 2019-10-29.
  24. ↑ Pereira, Philippe L.; Salvatore, Masala (April 2012). "Standards of Practice: Guidelines for Thermal Ablation of Primary and Secondary Lung Tumors". CardioVascular and Interventional Radiology. 35 (2): 247–254. doi: 10.1007/s00270-012-0340-1 . ISSN   1432-086X. PMID   22271076.
  25. ↑ Rivero, J. Ricardo; De La Cerda, Jose; Wang, Hanzhang; Liss, Michael A.; Farrell, Ann M.; Rodriguez, Ronald; Suri, Rajeev; Kaushik, Dharam (January 2018). "Partial Nephrectomy versus Thermal Ablation for Clinical Stage T1 Renal Masses: Systematic Review and Meta-Analysis of More than 3,900 Patients". Journal of Vascular and Interventional Radiology. 29 (1): 18–29. doi:10.1016/j.jvir.2017.08.013. ISSN   1535-7732. PMID   29102464.
  26. ↑ Foster, Ryan C.B.; Stavas, Joseph M. (June 2014). "Bone and Soft Tissue Ablation". Seminars in Interventional Radiology. 31 (2): 167–179. doi:10.1055/s-0034-1373791. ISSN   0739-9529. PMC   4078106 . PMID   25053865.
  27. ↑ Kurup, Anil Nicholas; Callstrom, Matthew R. (2013-12-01). "Ablation of Musculoskeletal Metastases: Pain Palliation, Fracture Risk Reduction, and Oligometastatic Disease". Techniques in Vascular & Interventional Radiology. 16 (4): 253–261. doi:10.1053/j.tvir.2013.08.007. ISSN   1089-2516. PMID   24238380.
  28. ↑ Nguyen, Tiffany; Hattery, Eleanor; Khatri, Vijay P. (May 2014). "Radiofrequency ablation and breast cancer: a review". Gland Surgery. 3 (2): 128–135. doi:10.3978/j.issn.2227-684X.2014.03.05. ISSN   2227-684X. PMC   4115759 . PMID   25083506.
  29. ↑ Martin, Robert C. G. (June 2015). "Use of irreversible electroporation in unresectable pancreatic cancer". Hepatobiliary Surgery and Nutrition. 4 (3): 211–215. doi:10.3978/j.issn.2304-3881.2015.01.10. ISSN   2304-3881. PMC   4465607 . PMID   26151062.
  30. ↑ Barney Brooks, The Treatment of Traumatic Arteriovenous Fistula, Southern Medical Journal. 01/1930; 23(2):100-106.
  31. ↑ Bown SG (1983). "Phototherapy in tumors". World Journal of Surgery. 7 (6): 700–709. doi:10.1007/BF01655209. PMID   6419477. S2CID   2574459.
  32. ↑ Deneve, Jeremiah L.; Choi, Junsung; et al. (December 2012). "Chemosaturation with Percutaneous Hepatic Perfusion for Unresectable Isolated Hepatic Metastases from Sarcoma". CardioVascular and Interventional Radiology. 35 (6): 1480–1487. doi:10.1007/s00270-012-0425-x. PMID   22699779. S2CID   25073546.
  33. ↑ "What is IO?". European Conference of Interventional Oncology. Cardiovascular and Interventional Radiological Society of Europe. Archived from the original on 2015-03-13.
  34. ↑ Adam, Andreas; Kenny, Lizbeth M. (2015). "Interventional oncology in multidisciplinary cancer treatment in the 21st century". Nature Reviews Clinical Oncology. 12 (2): 105–113. doi:10.1038/nrclinonc.2014.211. PMID   25445561. S2CID   7689364.
This page is based on this Wikipedia article
Text is available under the CC BY-SA 4.0 license; additional terms may apply.
Images, videos and audio are available under their respective licenses.