This technique takes advantage of the fact that HCC is a very vascular (contains many blood vessels) tumor and gets its blood supply exclusively from the branches of the hepatic artery. This procedure is similar to intra-arterial infusion of chemotherapy. But in TACE, there is the additional step of blocking (embolizing) the small blood vessels with different types of compounds, such as gelfoam or even small metal coils. Thus, TACE has the advantages of exposing the tumor to high concentrations of chemotherapy and confining the agents locally since they are not carried away by the blood stream. At the same time, this technique deprives the tumor of its needed blood supply, which can result in the damage or death of the tumor cells.There is no established standard protocol for TACE.If the procedure is successful (>50% lipiodol uptake in necrotic tumor demonstrated on the postprocedural CT scan), the embolization is repeated in 6-8 weeks. If the lipiodol uptake is less than 50%, the authors repeat the CT scan in 6-8 weeks. If the size of the tumor is reduced, repeat TACE may be considered.The second TACE treatment should first be performed in previously untreated tumors.The third treatment completes a normal course, but further treatments are performed in patients with residual disease.

The type and frequency of complications of TACE and intra-arterial chemotherapy are similar. The potential disadvantage of TACE is that blocking the feeding vessels to the tumor(s) may make future attempts at intra-arterial infusions impossible. Moreover, so far, there are no head-to-head studies directly comparing the effectiveness of intra-arterial infusion versus chemoembolization. Studies in Japan have shown that TACE can downstage HCC. In other words, the tumors shrank enough to lower (improve) the stage of the cancer. From the practical point of view, shrinking the tumor creates the option for surgery in some of these patients. Otherwise, these patients had tumors that were not operable (eligible for operation) because of the initial large size of their tumors. More importantly, these same studies showed an improvement in survival in patients whose tumors became considerably smaller. In the U.S., trials are underway to see whether doing TACE before liver transplantation increases patient survival as compared to liver transplantation without TACE.

It is safe to say that TACE or intra-arterial chemoinfusion are palliative treatment options for HCC. However, they are not curative (Fewer than 50% of patients will have some shrinkage in tumor size. Further, they can be used only in patients with relatively preserved liver function. Several randomized trials have established this procedure as standard of care for hepatocellular cacrinoma and neuroendocrine carcinoma.

There is little evidence on what drugs are best. Studies of mitomycin of adriamycin are most common but many radiologists add ethidiol based on a comparative study, of Gelfoam and some also use cisplatin, also based on a study. Combination of four drugs are often used, without much data. Another unanswered question under study is whether to combine TACE with chemotherapy or Nexavar.

Bercin Tarlan, Hayyam Kiratli, Current Treatment of Choroidal Melanoma, Expert Rev Ophthalmol. 2012;7(2):189-19

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EVIDENCE-BASED PRACTICE:
Calogero Cammà, Filippo Schepis, Ambrogio Orlando, Maddalena Albanese, Lillian Shahied, Franco Trevisani, Pietro Andreone, Antonio Craxì, and Mario Cottone
Transarterial Chemoembolization for Unresectable Hepatocellular Carcinoma: Meta-Analysis of Randomized Controlled Trials
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NCCN, melanoma, 2013

A similar drug is in a current trial: Randomized Phase I/II of RAD001 in Advanced Hepatocellular Carcinoma (HCC), NCT00390195

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Australia and New Zealand Horizon Scanning Network (2006) stated that PBT “may be of particular benefit” in the treatment of patients with intermediate depth tumors such as those in the head, cancers that are located in difficult or dangerous-to-treat areas, and tumors in locations where “conventional radiotherapy would damage surrounding tissue to an unacceptable level” (e.g., central nervous system and head). PBT “may be ideal for use in the treatment of pediatric patients where the need to avoid secondary tumors is important due to the potentially long life span after radiation treatment when they may develop radiation induced malignancies.7

A report by ASTRO’s Emerging Technologies Committee states that there is reason to be optimistic about the potential developments in proton beam therapy (PBT) and the prospective research that is ongoing at centers worldwide. Current data do not provide sufficient evidence to recommend PBT outside of clinical trials in lung cancer, head and neck cancer, GI malignancies (with the exception of HCC) and pediatric non-CNS malignancies. In hepatocellular carcinoma and prostate cancer, there is evidence of the efficacy of PBT but no suggestion that it is superior to photon based approaches. In pediatric CNS malignancies, there is a suggestion from the literature that PBT is superior to photon approaches, but there is currently insufficient data to support a firm recommendation for PBT. In the setting of craniospinal irradiation for pediatric patients, protons appear to offer a dosimetric benefit over photons but more clinical data are needed. In large ocular melanomas and chordomas, we believe that there is evidence for a benefit of PBT over photon approaches. In all fields, however, further clinical research is needed and should be encouraged (ASTRO, 2011).

ACR appropriateness criteria state that the physical characteristics of the proton beam would seem to allow for greater sparing of normal tissues, although there are unique concerns about its use for lung tumors. The small amount of clinical data on its use consists of small single institution series. These data as a whole can be challenging to interpret, as various different techniques have been used by these institutions, making comparisons between studies difficult. Results from larger, prospective, controlled trials that are underway will clarify the role of proton beam and other particle therapies for lung cancer (ACR, 2010).4

A Blue Cross Blue Shield technology assessment evaluated health outcomes following proton beam therapy (PBT) compared to stereotactic body radiotherapy (SBRT) for the management of Proton Beam Radiation Therapy: Medical Policy 12 non-small-cell lung cancer. The report concluded that, overall, evidence is insufficient to permit conclusions about the results of PBT for any stage of non-small-cell lung cancer. All PBT studies are case series, and there are no studies directly comparing proton beam therapy (PBT) and stereotactic body radiotherapy (SBRT). In the absence of randomized, controlled trials, the comparative effectiveness of PBT and SBRT is uncertain (BCBS, 2011).6

The only guideline that I found that offers a qualified support is NCCN. The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints 5

It is quite clear from limited studies that proton beam is not inferior to other radiotherapy techniques. What has not been proven is that it is superior and that its ability to spare the tissues translates to a better outcome. It makes sense that it should, but in science that would be called a hypothesis that needs to be proven. This si especially so for ehad and neck, where there is less consensus than in prostate cancer. Because PBT is only available in limited centers and is much more complex and expensive than other tissue sparing radiation therapy techniques, it should still be considered investigational.

ANal Cacner

ASTRO PBT July 2017 policy that supports Proton Beam in this situation, given the comparative dose distribution plan.The National Comprehensive Cancer Network (NCCN) states that the use of more advanced radiation technologies, such as proton therapy, is appropriate when needed to deliver adequate tumor doses while respecting normal tissue dose constraints. The ability of precision therapy to reduce toxicity
was demonstrated in RTOG 0529 which prospectively implemented dose-painted intensity modulated radiation therapy (IMRT) in a phase II trial design. Additionally, some studies have suggested that long-term outcomes are associated with time to completion of therapy and radiation dose

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2.Agency for Healthcare Research and Quality (AHRQ). Technology Assessment. Comparative
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2010. Available at: http://www.cms.gov/coveragegeninfo/downloads/id69ta.pdf.

3.Agency for Healthcare Research and Quality (AHRQ). Trikalinos TA, Terasawa T, Ip S, Raman
G, Lau J. Particle Beam Radiation Therapies for Cancer. Technical Brief No. 1. (Prepared by
Tufts Medical Center Evidence-based Practice Center under Contract No. HHSA-290-07-10055.)
Rockville, MD: AHRQ. Revised November 2009. Available at:
http://www.effectivehealthcare.ahrq.gov/ehc/products/58/173/particle%20beam%20mainreptrev1 1-09(r).pdf.

4.American College of Radiology (ACR). ACR Appropriateness Criteria. Nonsurgical treatment for non-small-cell lung cancer. 2010. Available at: http://www.acr.org/ac.

5.American Society for Radiation Oncology (ASTRO). Emerging Technologies Committee. An
evaluation of proton beam therapy. June 2011. Available at:

http://www.astro.org/HealthPolicy/EmergingTechnology/EvaluationProjects/documents/ProtonBea

mReport.pdf.

6.Blue Cross Blue Shield Association (BCBSA). Proton beam therapy for non-small-cell lung cancer. TEC Assessment, October 2010.

7.Purins A, Mundy L, Hiller J. Boron neutron capture therapy for cancer treatment. Horizon Scanning Prioritising Summary. Adelaide, SA: Adelaide Health Technology Assessment (AHTA); October 2007.

Semin Radiat Oncol. 2018 Apr;28(2):97-107.

Tian X, Liu K, Hou Y, Cheng J, Zhang J. The evolution of proton beam therapy: Current and future status. Mol Clin Oncol. 2017;8(1):15-21.

Anal Cancer

E.J. Vaios et al, Proton beam radiotherapy for anal and rectal cancers. J Gastrointest Oncol 2020;11(1):176-186

Kachnic LA, Winter K, Myerson RJ, et al. RTOG 0529: A phase 2 evaluation of dose-painted intensity modulated
radiation therapy in combination with 5-fluorouracil and mitomycin-C for the reduction of acute morbidity in
carcinoma of the anal canal. Int J Radiat Oncol Biol Phys 2013;86:27-33.

Ghosn M, Kourie HR, Abdayem P, et al. Anal cancer treatment: Current status and future perspectives. World J
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Press, Robert H et al. “Clinical Review of Proton Therapy in the Treatment of Unilateral Head and Neck Cancers.” International journal of particle therapy vol. 8,1 248-260. 25 Jun. 2021, doi:10.14338/IJPT-D-20-00055.1