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Posts Tagged ‘liver metastasis’


Author: Tilda Barliya PhD

Metastasis is a complex series of steps in which cancer cells leave the original tumor site and migrate to a distant organ. Certain cancers tend to spread to specific organ sites; however, the underlying mechanism is not completely understood. After lymph nodes, the liver is the most common site for colorectal cancer metastasis, and liver metastasis is a common cause of cancer-related mortality. Understanding the mechanisms and genetic alterations that predispose to the metastatic phenotype in colorectal cancer is imperative for early detection, prevention and treatment (1). Studies reveal that genomic instability in cancer cells leads to cellular heterogeneity, which may guide tumor cell aggression and specific organ colonization during the metastatic process.

Nat Clin Pract Oncol. 2008;5(4):206-219.

In 2008, Patricia S Steeg, Dan Theodorescu have published a great overview on the cancer metastases (1a).  Figure 1 represents Molecular distinctions between primary colorectal carcinomas and their liver metastases.

Studies have identified distinct expression trends at the RNA or protein levels in primary tumors and metastases, including genes that control metastasis (MTA1, N-Wasp, NCAML1), extracellular matrix function (fibronectin, collagens), microtubule dynamics (stathmin), transcription (Snail), drug-processing enzymes (DPD, TS) and kinases (Yes1).

It is worth mentioning that not every overexpressed or mutated gene is directly and primarily correlated with tumor metastases.

In order to answer this question, Ding Q and colleagues (1b) have done a great job identifying the gene expression signature for colorectal cancer liver metastases. Using an orthotopic colorectal cancer mouse model and transcriptomic microarray analysis, they found that 4 major genes are essential in mediating CRC-liver metastasesAPOBEC3GCD133LIPC, and S100P.

APOBEC3G– Is an apolipoprotein B mRNA-editing enzyme that has been suggested to play a role in the innate anti-viral immune system. Notably, this is the first time it has been shown that APOBEC3G, a gene involved in RNA editing, is able to promote tumor metastasis. APOBEC3G may downregulate miR-29 expression and hamper miR-29 activity in repressing MMP2.

CD133 – is a glycoprotein that is expressed in hematopoetic stem cells, endothelial progenitor cells, intestinal stem cells as well as saeveral types of tumor stem cells. It was related to a high incidence of metastasis in cholangiocarcinoma and melanoma has been indicated, However, questions regarding how CD133 is involved in metastasis and in which cancer stages, how CD133 expression is regulated, and what controls the transition of CD133+ to CD133– cells remain to be addressed.

LIPC –  is Hepatic Triacylglycerol Lipase. It is expressed in the liver and adrenal gland. One of the principal functions of hepatic lipase is to convert intermediate-low density lipoprotein (IDL) to low-density lipoprotein (LDL). A recent study also implicates a role for monoacylglycerol lipase in promoting tumor growth, migration, and invasion, as this lipase translates lipogenic phenotype to oncogenic signals in tumor cells.

S100P –  S100 proteins are localized in the cytoplasm and/or nucleus of a wide range of cells, and involved in the regulation of a number of cellular processes such as cell cycle progression and differentiation.  This protein may paly a role in the etiology of prostate cancer.

The authors (1b) found that overexpressing of these 4 genes increases the invasion and migration abilities of the SW620-control cells (= lymph node metastatic cell line) in vitro and also significantly enhances the frequency of hepatic metastasis in vivo (1b).

To determine the clinical correlation of our identified gene signatures with colorectal cancer hepatic metastasis, the authors examined the protein levels of APOBEC3GCD133LIPC, and S100P in 7 freshly isolated human colorectal cancer hepatic metastatic tumors and 7 nonmetastatic primary colorectal carcinomas. We showed that expression levels of these 4 genes are significantly increased in the metastatic tumors compared with the nonmetastatic primary tumors (1b).

Knocking down either one of these genes was not sufficient to decrease the liver metastasis rate in the orthotopic animal model, if compared with knocking down all 4 genes, indicating that the process of liver metastasis may require the cooperation/synergism of the 4 genes.

EGFR  was also identified to be a potential key player for liver metastases. There is somewhat conflicting data regarding the importance or use of EGF as an indicator for liver metasteses.  While some clinical protocols suggest patients with KRAS wild-type should be considered for combination therapy with EGFR inhibitors, because this strategy has led to promising results with improved R0 resection (2), others have shown that EGFR expression in the primary tumor site was not predictive of its level in the metastasis. EGFR expression levels in the primaries and in the metastases do not appear to be useful prognostic markers (3).

Additionally, recent studies also revealed that certain genes and signaling pathways might play a role in colon cancer liver metastasis. Metastasis-associated in colon cancer-1 (Macc1) was identified as a key regulator of HGF-MET signaling and is able to enhance colon cancer cell migration in vitro and liver metastasis in mouse model. TGF-β/Smad4 signaling was found to suppresses colon cancer metastasis in mice and the balance between Smad4/Smad7 and the TGF-β pathway in colorectal cancer may be critical for the metastatic process (1b).

Wulfkuhle and colleagues recently published an innovative study comparing the proteomic profiles of hepatic metastases generated by tumors from different primary organ sites. They strongly suggest that the microenviornment of the host organ plays a pivotal role in the activation of specific survival pathways (4).

The role of microenvironment and heterogeneity is reviewed by Bert Vogelstein  and colleagues in their outstanding paper on the Cancer Genome Landscape (5). They outline the multiplex orchestra of genes and their mutations that play role in cancer initiation, progressions and invasion into new metastatic niches,

In summary:

Many of the molecular pathways that promote tumorigenesis also promote metastasis and are important in the treatment of both aspects of cancer progression. This is a multiplex process that involves alternations/mutations in many genes and metastases, much like primary tumors, varies within a single patient and between patient.  The biology of liver metastases has been intensively investigated and several  genes where identified yet, one must remember that these set of gene may be true to one source of primary tumor origin and not not to another.  From a technical standpoint, the development of new and improved methods for early detection and prevention will not be easy, but there is no reason to assume that it will be more difficult than the development of new therapies aimed at treating widely metastatic disease. For further review on concurrent treatments for colorectal liver metastases, please go to liver metastases_treatments (I)

References:

1a. Patricia S Steeg, Dan Theodorescu. Metastasis: A Therapeutic Target for Cancer. Nat Clin Pract Oncol. 2008;5(4):206-219. http://www.medscape.com/viewarticle/571455_2.

1b. Qingqing Ding, Chun-Ju Chang, Xiaoming Xie, Weiya Xia, Jer-Yen Yang ,Shao-Chun Wang, Yan Wang, Jiahong Xia, Libo Chen, Changchun Cai, Huabin Li, Chia-Jui Yen, Hsu-Ping Kuo, Dung-Fang Lee, Jingyu Lang, Longfei Huo,Xiaoyun Cheng, Yun-Ju Chen, Chia-Wei Li, Long-Bin Jeng, Jennifer L. Hsu, Long-Yuan Li , Alai Tan, Steven A. Curley, Lee M. Ellis, Raymond N. DuBois and Mien-Chie Hung. APOBEC3G promotes liver metastasis in an orthotopic mouse model of colorectal cancer and predicts human hepatic metastasis. J Clin Invest. 2011;121(11):4526–4536. doi:10.1172/JCI45008. http://www.jci.org/articles/view/45008

2. Macelo R.S Cruz and Gilberto de Lima Lopes. Colon Cancer Liver Metastasis: Addition of Antiangiogenesis or EGFR Inhibitors to Chemotherapy. Current Colorectal Cancer Reports March 2013, 9(1); pp 68-73. http://link.springer.com/article/10.1007%2Fs11888-012-0148-z

3. Nirit Yarom N, Celia Marginean, Terence Moyana, Ivan Gorn-Hondermann , H. Chaim Birnboim, Horia Marginean, Rebecca C. Auer, Micheal Vickers, Timothy R. Asmis, Jean Maroun, Derek Jonker EGFR expression variance in paired colorectal cancer primary and metastatic tumors. Cancer Biol Ther 2010 Sep 1;10(5):416-421. https://www.landesbioscience.com/journals/cbt/article/12610/

4. Wulfkuhle J, Espina V, Liotta L, Petricoin E. Genomic and proteomic technologies for individualisation and improvement of cancer treatment. Eur J Cancer. 2004 Nov;40(17):2623-2632. http://www.ncbi.nlm.nih.gov/pubmed/15541963.

5. Bert Vogelstein, Nickolas Papadopoulos, Victor E. Velculescu, Shibin Zhou, Luis A. Diaz Jr., Kenneth W. Kinzler. Cancer Genome Landscapes. Science 29 March 2013:  Vol. 339 no. 6127 pp. 1546-1558  http://www.sciencemag.org/content/339/6127/1546.full

Other articles from our open access journal:

I. By Tilda Barliya PhD. Liver metastases_treatments. https://pharmaceuticalintelligence.com/2013/08/10/liver-metastasis/

II. By Tilda Barliya PhD. Cancer metastasis. https://pharmaceuticalintelligence.com/2013/07/06/cancer-metastasis/

III. By. Tilda Barliya PhD. Colon Cancer. https://pharmaceuticalintelligence.com/2013/04/30/colon-cancer/

IV. By. Stephen J. Williams. Issues in Personalized Medicine in Cancer: Intratumor Heterogeneity and Branched Evolution Revealed by Multiregion Sequencing. https://pharmaceuticalintelligence.com/2013/04/10/issues-in-personalized-medicine-in-cancer-intratumor-heterogeneity-and-branched-evolution-revealed-by-multiregion-sequencing/

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Author Tilda Barliya PhD

Hepatic metastatic disease from colorectal cancer (CRC) is a significant clinical problem. The liver is the dominant metastatic site for patients with CRC, and although two-thirds of affected patients have extrahepatic spread, some have disease that is isolated to the liver. For patients with isolated liver metastases, regional treatment approaches may be considered as an alternative to systemic chemotherapy (1).

Metastases from CRC most commonly develop within 2 years of resection of the primary tumor and are usually asymptomatic; rarely, patients may complain of vague upper abdominal pain. Hepatic metastases associated with CRC may occur regardless of the initial stage of the primary tumor although nodepositive primary lesions are more likely to precede hepatic metastasis (2).

The available regional treatments for hepatic metastases from CRC include (1):

  • Surgical resection
  • Local tumor ablation (ie, instillation of alcohol or acetic acid directly into the metastatic lesions
  • Radiofrequency ablation [RFA])
  • Regional hepatic intraarterial chemotherapy or chemoembolization
  • Radiation therapy (RT)

**Among these treatments, only surgery is associated with a survival plateau.

Screening for Hepatic metastasis (3):

  • A biopsy may be indicated to confirm the diagnosis, depending upon the clinical picture. However, fine needle aspiration cytology has not been advocated as a screening test, because of its high risk of complications. It has been shown that the incidence of needle tract metastases is 0.4%-5.1% after fine needle aspiration and use of the procedure in abdominal tumors is fatal in 0.006%-0.031% of cases.  Most deaths are due to hemorrhage of liver tumors (3).
  • Laparoscopy has not been advocated as a screening test for colorectal liver metastases due to its invasiveness.
  • Imaging modalities, such as contrast enhanced computed tomography (CT), magnetic resonance imaging (MRI) and positron emission tomography CT (PET-CT), may establish the diagnosis of liver metastasis of colorectal cancer. However, it is more difficult to make the clinical diagnosis of early liver metastases of colorectal cancer due to the absence of typical symptoms or signs.
  • Serological examination including tumor and biochemical markers for liver function evaluation is routinely performed, though its accuracy is not high.  In that aspect, carcinoembryonic antigen (CEA) levels is elevated in 63% of patients, while the activity of alanine aminotransferase (ALT) and aspartate aminotransferase (AST) is increased in about 30% of patients with liver metastases of colorectal cancer.

Surgical Resection (1)

Resection offers the greatest likelihood of cure for patients with liver-isolated CRC. In surgical case series, five-year survival rates after resection range from 24 to 58 percent, averaging 40 percent and surgical mortality rates are generally <5 percent (1). It’s worth noted that subgroups with advanced age, comorbid disease, and synchronous hepatic and colon resection may have higher procedure-related mortality and worse long-term outcomes.

The five-year survival rate was only 25 percent, Even so, five-year survival rates with the most active systemic chemotherapy regimens are only 10 to 11 percent, only about one-fifth of whom have a sustained disease remission. More so, approximately one-third of five-year survivors suffer a cancer-related death, while those who survive 10 years appear to be cured (4).

Because of its clear survival impact, surgical resection is the treatment of choice when feasible. Unfortunately, no more than 20 percent of patients with isolated hepatic metastases are amenable to potentially curative resection. Most are not surgical candidates because of tumor size, location, multifocality, or inadequate hepatic reserve.

Patient candidates for resection – The criteria for resectability differ among individual liver surgeons regarding borderline cases, from center to center and from country to country. One consensus statement defined absolute unresectability as nontreatable extrahepatic disease, unfitness for surgery, or involvement of more than 70 percent of the liver or six segments (1,2).  Patients are evaluaed using preoperative liver MRI and intraoperative ultrasound which offer the optimal assessment of the number, size, and proximity of tumors to key vascular and biliary structures.

Modern multidisciplinary consensus for resectable CRC liver metastases:

  • Tumors that can be resected completely (leaving an adequate liver remnant)
  • No  involvement of the hepatic artery, major bile ducts, main portal vein, orceliac/paraaortic lymph nodes
  • Adequate predicted functional hepatic reserve postresection

Criteria for unresectable liver metastases (5):

  • Pateitns with more than three lesions, those
  • Patients with bilobar distribution (ie, tumor involving any segments of the left and right hemi-liver),
  • Patients in whom it was not possible to achieve 1 cm margins,
  • Patients with portal lymph node or other extrahepatic metastases, and
  • Patients with liver metastases from cancers other than colorectal tumors

Some of these exclusion criteria have been challenged.

  • Better and safer surgical techniques are now more suitable for patients with multiple, even bilobar tumors.
  • A two-stage approach to hepatic resection may be needed in the presence of multiple bilobar metastases
  • Achieving wide margins doesn’t increase the 5-year survival. **** Only patients with a positive margin had worse survival and a higher intrahepatic recurrence rate.
  • Presence of portal lymph node metastases – still been challenged and results are controversy.
  • A major problem is the prediction of metastatic lymph nodes in the hepatic pedicle in patients with CRC liver metastases.  The presence of portal node metastases is not inevitably associated with distant metastases.  Outcome was more favorable if nodal involvement was limited to the porta as compared to along the common hepatic artery.
  • The presence of other sites of limited extrahepatic metastases (particularly lung) should not be considered a contraindication to resection as long as the disease is amenable to complete extirpation. However, outcomes in this group are not as favorable, particularly when there are >6 liver metastases.

Diagnostic Laparoscopy

In modern treatment paradigms, laparoscopy is infrequently performed, particularly since many patients have undergone surgical exploration of the peritoneum at the time of resection of a synchronous primary tumor. Laparoscopy is usually reserved for those thought to be at the highest risk for occult metastatic disease.

A growing number of authors report that staging laparoscopy (including laparoscopic US) performed under general anesthesia just prior to planned resection will identify 16 to 64 percent of patients with unresectable disease.

This approach is particularly useful in identifying small peritoneal metastases, additional hepatic metastases, and unsuspected cirrhosis. Laparoscopy in this setting is less likely to identify lymph node metastases, vascular compromise, and extensive biliary involvement that might render a patient unresectable (2,6).

Neoadjuvant chemotherapy

The availability of increasingly effective systemic chemotherapy has prompted interest in preoperative or neoadjuvant systemic chemotherapy prior to liver resection.  It may  be considered as a means of “downsizing” liver metastases prior to resection to lessen the complexity of hepatic metastasectomy or for initially unresectable metastatic disease (1). Chemotherapy, has many side effects including liver toxicity such as:  steatosis (chemotherapy-associated steatohepatitis, CASH), vascular injury, and nodular regenerative hyperplasia in the livers.

Due to high number of patients with liver toxicity and morbidity, these instructions have been suggested:

  • For low-risk (medically fit, four or fewer lesions), potentially resectable patients, initial surgery rather than neoadjuvant chemotherapy should be chosen, followed by postoperative chemotherapy.
  • For patients who have higher risk, borderline resectable or unresectable disease, neoadjuvant chemotherapy is the preferred approach.

Neoadjuvant Chemotherapy Guidelines from the National Comprehensive Cancer Network (NCCN) suggest any of the following:

  • FOLFOX or CAPOX or FOLFIRI with or without bevacizumab or
  • FOLFOX or CAPOX or FOLFIRI plus cetuximab (wild-type K-ras only) or
  • FOLFOXIRI alone

Bevacizumab – Its addition to traditional chemotherapy results in a modestly higher frequency of tumor regression compared to regimens that do not include bevacizumab. However, these benefits have come at the cost of significant treatment-related toxicity. Such as: such as stroke and arterial thromboembolic events, bowel perforation and bleeding.  Data regarding the need and timing of use of bevacizumab is somewhat conflicting.

Cetuximab (if K-ras wild type) and panitumumab (if K-ras wild type) are also suggested as part of the  chemotherapy regimen in certain clinics are regional dependent.

Intraarterial (HIA) chemotherapy – The administration of chemotherapy into the hepatic artery. The benefit of this approach is remains unclear. A combined approach of HIA floxuridine plus systemic chemotherapy (oxaliplatin plus irinotecan) was explored in a single institution study of 49 patients with initially unresectable CRC liver metastases. Overall, 92 percent had either a complete or partial response rate to chemotherapy, and 23 (43 percent) were able to undergo a later resection, 19 with negative margins. The median overall survival from pump placement for the entire cohort was 40 months (1, 7).  Another approach is HIA oxaliplatin combined with systemic 5-FU and leucovorin for patients with initially unresectable but isolated hepatic CRC metastasis.

It should be noted that this approach is not used by many clinicians outside of New York City. The only way to assess the contribution of HIA chemotherapy to neoadjuvant systemic chemotherapy is with a randomized controlled trial.

Portal vein infusion — Because HIA FUDR carries a risk for biliary sclerosis, administration into the portal vein has been explored as an alternative. hepatic micrometastases (as well as the biliary tree) are primarily dependent on the portal vein for their blood supply. Like HIA infusion, portal vein infusion (PVI) carries with it a significant regional exposure advantage.

The potential benefit of adjuvant PVI with FUDR after resection or ablation of isolated hepatic metastases was evaluated in two trials conducted at the City of Hope Medical Center (1, 8).  The benefit of this approach was somewhat lower than has been reported with HIA FUDR and systemic 5-FU. Therefore, the use of this approach is limited.

Hepatic radiotherapy — The use of external beam radiotherapy and internal application of radiation therapy through the use of yttrium-labeled microspheres.  Radiation therapy (RT) has traditionally had a limited role in the treatment of liver tumors, primarily because of the low whole-organ tolerance of the liver to radiation (9).   When radiation is applied to the entire liver, RT doses of 30 to 33 Gy carry about a 5% risk of radiation-induced liver disease (RILD). The risk rises rapidly, such that by 40 Gy, the risk is approximately 50%.  Considering that most solid tumors require RT doses higher than 60 Gy to provide a reasonable chance for local control, it is not surprising that wholeorgan liver RT provides only a modest palliative benefit rather than durable tumor control. Hepatic dysfunction after RT is a very frequent event.

Summary:

Liver metastasis are a very tough disease to battle and the outcome is not encouraging. Currently, surgical resection is the only potentially curative option for patients with liver-isolated metastatic colorectal cancer. For appropriately selected patients with four or fewer metastases, five-year relapse-free survival rates average 30 percent.  Diagnostic laparoscopy is suggested only in patients with a suspicion of low-volume carcinomatosis based on preoperative radiographic imaging and for selected other cases at high risk for intraperitoneal metastatic disease. The optimal chemotherapy regimen is still not fully established but some suggestions have been made and the benefits of using HIA is still not clear.

Standardization of scoring, timing, surgical techniques , results from clinical trials and advanced research will offer better hope for these patients, who now, have a very bad prognosis and survival rates.

Reference:

1.  Venook AP and Curley SA. Management of potentially resectable colorectal cancer liver metastases. UpToDate Jun 2013. http://www.uptodate.com/contents/management-of-potentially-resectable-colorectal-cancer-liver-metastases

2. Smith AJ., DeMatteo RP., Fong Y and Blumgart LH.  Metastatic Liver Cancer.  HEPATOBILIARY CANCER. http://web.squ.edu.om/med-Lib/MED_CD/E_CDs/Hepatobiliary%20Cancer/DOCS/Ch4.pdf

3. Wu XZ., Ma F., and Wang XL. Serological diagnostic factors for liver metastasis in patients with colorectal cancer. World J Gastroenterol. 2010 August 28; 16(32): 4084–4088. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2928464/

4. Tomlinson JS, Jarnagin WR, DeMatteo RP, Fong Y, Kornprat P, Gonen M, Kemeny N, Brennan MF, Blumgart LH, D’Angelica M. Actual 10-year survival after resection of colorectal liver metastases defines cure. J Clin Oncol. 2007;25(29):4575. http://www.ncbi.nlm.nih.gov/pubmed?term=17925551

5. Tanabe KK. Palliative liver resections. J Surg Oncol. 2002;80(2):69. http://onlinelibrary.wiley.com/doi/10.1002/jso.10108/abstract;jsessionid=F19964733A4A1A2708A0BA0E274CF586.d01t03

6.  Ravikumar TS. Laparoscopic staging and intraoperative ultrasonography for liver tumor management. Surg Oncol Clin N Am 1996;5:271–282. http://www.ncbi.nlm.nih.gov/pubmed/9019351

7, Kemeny NE, Melendez FD, Capanu M, Paty PB, Fong Y, Schwartz LH, Jarnagin WR, Patel D, D’Angelica M.  Conversion to resectability using hepatic artery infusion plus systemic chemotherapy for the treatment of unresectable liver metastases from colorectal carcinoma. J Clin Oncol. 2009;27(21):3465. http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3646304/

8.  Faynsod M, Wagman LD, Longmate J, Carroll M, Leong LA. Improved hepatic toxicity profile of portal vein adjuvant hepatic infusional chemotherapy.J Clin Oncol. 2005;23(22):4876. http://www.ncbi.nlm.nih.gov/pubmed?term=16009960

9. I. Frank Ciernik and Theodore S. Lawrence. Radiation Therapy for Liver Tumors. Book: Systemic and Regional Therapies. Chapter 7.  http://www.jblearning.com/samples/0763718572/Chapter_07.pdf

Other articles from our open journal access

I.  By: Dr. Sudipta Saha PhD . Treatment for Endocrine Tumors and Side Effects. https://pharmaceuticalintelligence.com/2013/06/24/treatment-for-endocrine-tumors-and-side-effects/

II. By: Dr. Stephen J. Williams PhD. Differentiation Therapy – Epigenetics Tackles Solid Tumors. https://pharmaceuticalintelligence.com/2013/01/03/differentiation-therapy-epigenetics-tackles-solid-tumors/

III. By: Dr.  Ritu Saxena, PhD. In focus: Circulating Tumor Cells. https://pharmaceuticalintelligence.com/2013/06/24/in-focus-circulating-tumor-cells/

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Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma

Curator & Reporter: Dror Nir, PhD

Large organs like the liver are good candidates for focused treatment. The following paper:

Minimally invasive image-guided therapy for inoperable hepatocellular carcinoma: What is the evidence today?

By Beatrijs A. Seinstra1, et. al. published mid-2010, gives a review of the state-of-the-art of the then available methods for local lesions’ ablation. As far as ablation techniques availability, I have found this review very much relevant to today’s technological reality. It is worthwhile noting that in the last couple of years, new imaging-based navigation and guidance applications were introduced into the market holding a promise to improve the accuracy of administrating such treatment. These are subject to clinical validation in large clinical studies.  From the above mentioned publication I have chosen to highlight the parts discussing the importance of imaging-based guidance to the effective application of localized ablation-type therapies.

The clinical need:

Hepatocellular carcinoma (HCC) is a primary malignant tumor of the liver that accounts for an important health problem worldwide. Primary liver cancer is the sixth most common cancer worldwide with an incidence of 626,000 patients a year, and the third most common cause of cancer-related death [1]. Only 10–15% of HCC patients are suitable candidates for hepatic resection and liver transplantation due to the advanced stage of the disease at time of diagnosis and shortage of donors.

Immerging solution:

In order to provide therapeutic options for patients with inoperable HCC, several minimally invasive image-guided therapies for locoregional treatment have been developed. HCC has a tendency to remain confined to the liver until the disease has advanced, making these treatments particularly attractive.

Minimally invasive image-guided therapies can be divided into the group of the tumor ablative techniques or the group of image-guided catheter-based techniques. Tumor ablative techniques are either based on thermal tumor destruction, as in radiofrequency ablation (RFA), cryoablation, microwave ablation, laser ablation and high-intensity focused ultrasound (HIFU), or chemical tumor destruction, as in percutaneous ethanol injection (PEI). These techniques are mostly used for early stage disease. Image-guided catheter-based techniques rely on intra-arterial delivery of embolic, chemoembolic, or radioembolic agents [22]. These techniques enable treatment of large lesions or whole liver treatment, and are as such used for intermediate stage HCC (Figure 1).

Minimally invasive image-guided ablation techniques and intra-arterial interventions may prolong survival, spare more functioning liver tissue in comparison to surgical resection (which can be very important in cirrhotic patients), allow retreatment if necessary, and may be an effective bridge to transplantation [2327].

During the last 2 decades, minimally invasive image-guided therapies have revolutionized the management of inoperable HCC.

The value of image guidance

Accurate imaging is of great importance during minimally invasive loco-regional therapies to efficiently guide and monitor the treatment. It enables proper placement of instruments, like the probe in case of ablation or the catheter in case of intra-arterial therapy, and accurate monitoring of the progression of the necrotic zone during ablation.

can all be employed. In current clinical practice, placement of the catheter in intra-arterial procedures is usually performed under fluoroscopic guidance, while ablation may be guided by ultrasound, CT or MRI.

  • Ultrasound guidance allows probe insertion from every angle, offers real time visualization and correction for motion artifacts when targeting the tumor, and is low cost. However, the gas created during ablation (or ice in the case of cryoablation) hampers penetration of the ultrasound beams in tissue, causing acoustic shadowing and obscuring image details like the delineation between tumor borders and ablation zone.
  • CT is also frequently used to guide minimally invasive ablation therapy, and is a reliable modality to confirm treatment results. In comparison to US, it provides increased lesion discrimination, a more reliable depiction of ablated/non-ablated interfaces, and a better correlation to pathologic size [28]. However, due to its hypervascularity, small HCCs can only be clearly visualized in the arterial phase for a short period of time. Another disadvantage of CT is the exposure of the patient and physician to ionizing radiation.
  • Combining US imaging for probe placement and CT for ablation monitoring reduces this exposure. At the moment, hybrid systems are being developed, enabling combination of imaging techniques, like ultrasound and CT imaging, thereby improving the registration accuracy during treatment [29]. The interest in MRI-guided ablation is growing, as it produces a high-quality image allowing high-sensitivity tumor detection and accurate identification of the target region with multiplanar imaging.
  • MRI also enables real-time monitoring of the temperature evolution during treatment [3035]. However, MRI is an expensive technique, and MRI-guided ablation is still limited in clinical practice. Currently, the most widely used ablation technique for percutaneous treatment of focal hepatic malignancies is radiofrequency ablation (RFA), which has been shown to be safe and effective for the treatment of early stage HCC [4850]. During RFA, a small electrode is placed within the tumor, and a high-frequency alternating electric current (approximately 400 MHz) is generated, causing ionic agitation within the tissue. ….. Most frequently ultrasound is used for image guidance (Figs. 23), but there are reports of groups who use CT, MRI, or fluoroscopic imaging.
Ultrasound guided RFA. a: HCC lesion in a non-surgical patient pre-treatment (pointed out by arrow). b: Just after start treatment, electrode placed centrally in the tumor. c: Gas formation during ablation causes acoustic shadowing

Ultrasound guided RFA. a: HCC lesion in a non-surgical patient pre-treatment (pointed out by arrow). b: Just after start treatment, electrode placed centrally in the tumor. c: Gas formation during ablation causes acoustic shadowing

Contrast-enhanced CT pre- and post-RFA. Same patient as in Fig. 2. a: Hypervascular lesion (biopsy proven HCC) in right liver lobe (pointed out by arrow) before treatment. b: Ablated lesion directly post ablation, with reactive hyperemia around the RFA lesion

Contrast-enhanced CT pre- and post-RFA. Same patient as in Fig. 2. a: Hypervascular lesion (biopsy proven HCC) in right liver lobe (pointed out by arrow) before treatment. b: Ablated lesion directly post ablation, with reactive hyperemia around the RFA lesion

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El-Serag HB, Davila JA, Petersen NJ, McGlynn KA (2003) The continuing increase in the incidence of hepatocellular carcinoma in the United States: an update. Ann Intern Med 139:817–823PubMed

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Chen HL, Chang MH, Ni YH, Hsu HY, Lee PI, Lee CY et al (1996) Seroepidemiology of hepatitis B virus infection in children: Ten years of mass vaccination in Taiwan. JAMA 276:906–908PubMedCrossRef

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Chang MH, Chen CJ, Lai MS, Hsu HM, Wu TC, Kong MS et al (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N Engl J Med 336:1855–1859PubMedCrossRef

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Adami HO, Hsing AW, McLaughlin JK, Trichopoulos D, Hacker D, Ekbom A et al (1992) Alcoholism and liver cirrhosis in the etiology of primary liver cancer. Int J Cancer 51:898–902PubMedCrossRef

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Bruix J, Barrera JM, Calvet X, Ercilla G, Costa J, Sanchez-Tapias JM et al (1989) Prevalence of antibodies to hepatitis C virus in Spanish patients with hepatocellular carcinoma and hepatic cirrhosis. Lancet 2:1004–1006PubMedCrossRef

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State of the art in oncologic imaging of Colorectal cancers.

Author-Writer: Dror Nir, PhD

This is the fourth post in a series in which I will address the state of the art in oncologic imaging based on a review paper; Advances in oncologic imaging that provides updates on the latest approaches to imaging of 5 common cancers: breast, lung, prostate, colorectal cancers, and lymphoma. This paper is published at CA Cancer J Clin 2012. © 2012 American Cancer Society.

The paper gives a fair description of the use of imaging in interventional oncology based on literature review of more than 200 peer-reviewed publications. In this post I summaries the chapter on colorectal cancer imaging. It reviews current and developing radiologic practices in CRC with respect to screening, preoperative evaluation, surveillance, and post-treatment re-staging.

Colorectal cancer (CRC) is an example to successful imaging-based screening evident by noticeable reduction in mortality rates. The 5-year survival rate of CRC patients diagnosed at an early stage is 90%.1 121 According to this review; “(CRC) is the third most common cancer worldwide and the second most frequent cause of cancer death in the United States. The American Cancer Society estimates that 143,460 new cases of CRC will be diagnosed and 51,690 deaths from CRC will occur in the United States in 2012.120 Because of screening and removal of premalignant polyps, incidence rates have declined over the last 3 decades.

The authors found out that the increased use of CT in CRC screening has the potential of reducing its costs and associated tisks 122 In addition, use of DW-MRI enabled better outcomes of CRC liver metastasis treatment as it enables tailored localized treatment of such lesions.123 124 Finally, the authors found that: “MRI for staging of rectal cancer has become standard practice and, in some instances, is performed in lieu of surgeon-performed endorectal US (ERUS), providing the radiologist with an even greater role in the management of patients with CRC.125 “

 Screening

CRC is a largely preventable disease, as the progression of the adenoma-carcinoma sequence of mutations is slow and leaves ample time to intervene. Nonetheless, approximately 41% of the population (in the USA) eligible for screening remains unscreened. 126 Most screening is performed using non-imaging tests”

Any of these screening strategies will reduce mortality from CRC.126127 

Among imaging tests used for screening, barium enema has seen a continual decline in usage, at least in part due to the landmark study showing that this test detected only 39% of polyps identified at colonoscopy, including only 48% of those > 1 cm in size.131 The recent (and largest, with > 2500 patients) multicenter CT colonography (CTC, also known as virtual colonoscopy) screening study, performed by the American College of Radiology Imaging Network, found that CTC had sensitivity of 90% and similar specificity for polyps > 9 mm, and the number of centers using CTC has increased.122 Widespread deployment of CTC remains hindered, in part, by the 2009 decision of the Center for Medicare and Medicaid Service (CMS) to deny reimbursement based on 1) potential radiation risk, 2) impact of detection of extracolonic findings, and 3) efficacy in the 65 years and older age group of concern to CMS. Data from studies reported after this decision put CTC in a good position to be reconsidered for reimbursement. The median estimated effective dose is currently 5 to 6 mSv, a dose far less than that received from a standard CT exam and even comparable to or lower than that received from a barium enema examination. In fact, the radiation dose from CTC is equivalent to that received from cosmic radiation in a 1-year period.132 Extra-colonic findings occur in 7% to 11% of cases and lead to extra examinations in about 6% with a relevant new diagnosis made in 2.5%, according to the experience of the largest screening center in the United States.133 Furthermore, when detection of extracolonic cancers and aortoiliac aneurysms is included along with CRC screening, CT colonography (CTC) has been shown to be more clinically effective and more cost-effective than optical colonoscopy.134 In an observational study, CTC accuracy was maintained in patients aged 65 to 79 years, who were compared to the overall general population sample. In the older patients, CTC remained a safe and effective modality and program outcome measures, such as colonoscopy referral and extracolonic work-up rates, remained similar to those in other screened groups.135

 Detection and Characterization

Diagnosis and clinical staging of primary colonic adenocarcinoma is most often accomplished by combining colonoscopy with biopsy and performing cross-sectional imaging to detect metastatic disease.

Although CT and MRI are widely used for preoperative whole-body staging, they are not recommended first-line methods for detection of primary lesions. In contradistinction, CTC has matured into an excellent diagnostic method for detection of CRC. Data drawn largely from screening studies tell us that its sensitivity for polyps > 10 mm is 90% or greater, and that it will detect nearly every cancer. In fact, a recent meta-analysis of more than 11,000 patients indicated that CTC had sensitivity of 96.1% (398 of 414) for CRC, and when cathartic cleansing and fecal tagging were used, no cancers were missed (Fig. 16).137 Detection of flat cancers remains a challenge with CTC as compared with endoscopic methods in which mucosal surface details are better appreciated. CTC not only detects CRC, but with its cross-sectional depiction also allows characterization of tumors using the TNM staging system138 with reasonable T- and N-stage accuracies of 83% and 80%, respectively.139 CTC is an operator-dependent technique that has shown great variability between radiologists with different degrees of training. Computer-aided detection (CAD) was developed for this reason and because 10,000 to 15,000 images must be scrutinized for each large adenoma detected. In a screening cohort of 3077 consecutive asymptomatic adults, stand-alone CAD had sensitivities of 97% and 100% for advanced neoplasia and cancer, respectively.140

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Coronal reformatted CT scan of the abdomen and pelvis shows a left colon primary adenocarcinoma causing colonic obstruction.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

Three-dimensional rendering from CT colonography shows a right colon adenocarcinoma which was stage T1N0.

With magnetic resonance colonography (MRC), detection of masses is limited because techniques employing air cause susceptibility artifacts, and those employing dark-lumen techniques with water-filling and intravenous gadolinium are under scrutiny because of concerns about the potential risk of nephrogenic systemic fibrosis. In addition, in the largest screening study, the sensitivity of MRC was only 70% in patients with colorectal lesions more than 10 mm in size.141

Imaging plays a critical role in detecting liver metastases in order to properly stage and treat the patient with colorectal cancer. NCCN guidelines recommend contrast-enhanced CT or MRI.142 “

MRI is the most promising imaging modality for management of rectal cancer.

Staging of this cancer is primarily accomplished with US, typically performed by surgeons. MRI using phased-array coils provides complete visualization of the pelvic anatomy and, especially, the circumferential resection margin, an important landmark for the standard total mesorectal excision.

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

In an MRI of rectal carcinoma, the T2-weighted axial image shows rectal mass penetrating the wall and extending to the left posterolateral mesorectal fascia (also known as the circumferential resection margin).

 

 The MERCURY study125established the near equivalence of MRI to histopathology for identification of this margin, an important advantage of MRI over ERUS, with which the margin is not routinely visualized.147 T- and N- stage accuracies of MRI (87% and 74%, respectively) were similar to those of ERUS (82% and 74%, respectively).148 Accurate lymph node identification remains a problem for MRI. Toward this end, a new albumin-bound gadolinium agent has shown some promise, and further results are awaited.149

 Role of Imaging in Assessing Treatment Response

Imaging plays a critical role in 1) determining response to systemic and loco-regional treatment of liver metastases, 2) assessing response to local treatment and restaging rectal cancer primary lesions, and 3) detecting and assessing the treatment response of extra-hepatic metastatic disease. Systemic treatment (and in some centers, hepatic artery infusion) of non-resectable liver metastases with chemotherapy aims at reduction of the metastatic burden, which, occasionally may allow attempts at curative liver resection.

Due to the limitations of CT with regard to soft tissue contrast and fatty liver. MRI has greater sensitivity for remaining (or new) lesions < 1.0 cm due to its superior soft tissue contrast. In a recent meta-analysis of 25 eligible studies, MRI showed higher sensitivity than CT on a per-patient basis (P = .05) and on a per-lesion basis as well (P = .0001). With its 81.1% sensitivity and 97.2% specificity, MRI is thus the preferred modality.151 Nonetheless, under the current NCCN guidelines, CT remains the preferred modality.142 

Loco-regional (“liver-directed”) therapies include radiofrequency, microwave ablation, transarterial chemo- or particle embolization and irreversible electroporation. With these treatments, responding lesions can actually increase in size, and simple size criteria are no longer sufficient to determine response. The European Association for the Study of the Liver has issued new criteria to assess viability of remaining tumor based on enhancing residual volume by multiphase CT or MRI.152 However, the field is rapidly changing and there is no consensus on the optimal imaging strategy following loco-regional therapy.

Recent meta-analyses of randomized controlled trials comparing low-intensity and high-intensity surveillance programs have shown advantages for more intense follow-up in Stages I-III disease;170-173 however, controversies remain regarding the optimal surveillance strategy.

Lymphoma Imaging

To be followed…

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