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Posts Tagged ‘tumor ablation’


Ablation Techniques in Interventional Oncology

Author and Curator: Dror Nir, PhD

“Ablation is removal of material from the surface of an object by vaporization, chipping, or other erosive processes.”; WikipediA.

The use of ablative techniques in medicine is known for decades. By the late 90s, the ability to manipulate ablation sources and control their application to area of interest improved to a level that triggered their adaptation to cancer treatment. To date, ablation  is still a controversial treatment, yet steadily growing in it’s offerings to very specific cancer patients’ population.

The attractiveness in ablation as a form of cancer treatment is in the promise of minimal invasiveness, focused tissue destruction and better quality of life due to the ability to partially maintain viability of affected organs.  The main challenges preventing wider adaptation of ablative treatments are: the inability to noninvasively assess the level of cancerous tissue destruction during treatment; resulting in metastatic recurrence of the disease and the insufficient isolation of the treatment area from its surrounding.   This frequently results In addition, post-ablation salvage treatments are much more complicated. Since failed ablative treatment represents a lost opportunity to apply effective treatment to the primary tumor the current trend is to apply such treatments to low-grade cancers.

Nevertheless, the attractiveness of treating cancer in a focused way that preserves the long-term quality of life continuously feeds the development efforts and investments related to introduction of new and improved ablative treatments giving the hope that sometime in the future focused ablative treatment will reach its full potential.

The following paper reviews the main ablation techniques that are available for use today: Percutaneous image-guided ablation of bone and soft tissue tumours: a review of available techniques and protective measures.

Abstract

Background

Primary or metastatic osseous and soft tissue lesions can be treated by ablation techniques.

Methods

These techniques are classified into chemical ablation (including ethanol or acetic acid injection) and thermal ablation (including laser, radiofrequency, microwave, cryoablation, radiofrequency ionisation and MR-guided HIFU). Ablation can be performed either alone or in combination with surgical or other percutaneous techniques.

Results

In most cases, ablation provides curative treatment for benign lesions and malignant lesions up to 3 cm. Furthermore, it can be a palliative treatment providing pain reduction and local control of the disease, diminishing the tumor burden and mass effect on organs. Ablation may result in bone weakening; therefore, whenever stabilization is undermined, bone augmentation should follow ablation depending on the lesion size and location.

Conclusion

Thermal ablation of bone and soft tissues demonstrates high success and relatively low complication rates. However, the most common complication is the iatrogenic thermal damage of surrounding sensitive structures. Nervous structures are very sensitive to extremely high and low temperatures with resultant transient or permanent neurological damage. Thermal damage can cause normal bone osteonecrosis in the lesion’s periphery, surrounding muscular atrophy and scarring, and skin burns. Successful thermal ablation requires a sufficient ablation volume and thermal protection of the surrounding vulnerable structures.

Teaching points

Percutaneous ablations constitute a safe and efficacious therapy for treatment of osteoid osteoma.

Ablation techniques can treat painful malignant MSK lesions and provide local tumor control.

Thermal ablation of bone and soft tissues demonstrates high success and low complication rates.

Nerves, cartilage and skin are sensitive to extremely high and low temperatures.

Successful thermal ablation occasionally requires thermal protection of the surrounding structures.

For the purpose of this chapter we picked up three techniques:

Radiofrequency ablation

Straight or expandable percutaneously placed electrodes deliver a high-frequency alternating current, which causes ionic agitation with resultant frictional heat (temperatures of 60–100 ˚C) that produces protein denaturation and coagulation necrosis [8]. Concerning active protective techniques, all kinds of gas dissection can be performed. Hydrodissection is performed with dextrose 5 % (acts as an insulator as opposed to normal saline, which acts as a conductor). All kinds of skin cooling, thermal and neural monitoring can be performed.

 

Microwave ablation

Straight percutaneously placed antennae deliver electromagnetic microwaves (915 or 2,450 MHz) with resultant frictional heat (temperatures of 60–100 ˚C) that produces protein denaturation and coagulation necrosis [8]. Concerning active protective techniques, all kinds of gas dissection can be performed, whilst hydrodissection is usually avoided (MWA is based on agitation of water molecules for energy transmission). All kinds of skin cooling, thermal and neural monitoring can be performed.

Percutaneous ablation of malignant metastatic lesions is performed under imaging guidance, extended local sterility measures and antibiotic prophylaxis. Whenever the ablation zone is expected to extend up to 1 cm close to critical structures (e.g. the nerve root, skin, etc.), all the necessary thermal protection techniques should be applied (Fig. 3).

13244_2014_332_Fig3_HTML

a Painful soft tissue mass infiltrating the left T10 posterior rib. b A microwave antenna is percutaneously inserted inside the mass. Due to the proximity to the skin a sterile glove filled with cold water is placed over the skin. c CT axial scan 3 months

Irreversible Electroporation (IRE)

Each cell membrane point has a local transmembrane voltage that determines a dynamic phenomenon called electroporation (reversible or irreversible) [16]. Electroporation is manifested by specific transmembrane voltage thresholds related to a given pulse duration and shape. Thus, a threshold for an electronic field magnitude is defined and only cells with higher electric field magnitudes than this threshold are electroporated. IRE produces persistent nano-sized membrane pores compromising the viability of cells [16]. On the other hand, collagen and other supporting structures remain unaffected. The IRE generator produces direct current (25–45 A) electric pulses of high voltage (1,500–3,000 V).

Lastly we wish to highlight a method that is mostly used on patients diagnosed at intermediate or advanced clinical stages of Hepatocellular Carcinoma (HCC); transarterial chemoembolization  (TACE)

“Transcatheter arterial chemoembolization (also called transarterial chemoembolization or TACE) is a minimally invasive procedure performed in interventional radiology  to restrict a tumor’s blood supply. Small embolic particles coated with chemotherapeutic agents are injected selectively into an artery directly supplying a tumor. TACE derives its beneficial effect by two primary mechanisms. Most tumors within the liver are supplied by the proper hepatic artery, so arterial embolization preferentially interrupts the tumor’s blood supply and stalls growth until neovascularization. Secondly, focused administration of chemotherapy allows for delivery of a higher dose to the tissue while simultaneously reducing systemic exposure, which is typically the dose limiting factor. This effect is potentiated by the fact that the chemotherapeutic drug is not washed out from the tumor vascular bed by blood flow after embolization. Effectively, this results in a higher concentration of drug to be in contact with the tumor for a longer period of time. Park et al. conceptualized carcinogenesis of HCC as a multistep process involving parenchymal arterialization, sinusoidal capillarization, and development of unpaired arteries (a vital component of tumor angiogenesis). All these events lead to a gradual shift in tumor blood supply from portal to arterial circulation. This concept has been validated using dynamic imaging modalities by various investigators. Sigurdson et al. demonstrated that when an agent was infused via the hepatic artery, intratumoral concentrations were ten times greater compared to when agents were administered through the portal vein. Hence, arterial treatment targets the tumor while normal liver is relatively spared. Embolization induces ischemic necrosis of tumor causing a failure of the transmembrane pump, resulting in a greater absorption of agents by the tumor cells. Tissue concentration of agents within the tumor is greater than 40 times that of the surrounding normal liver.”; WikipediA

A recent open access research paper: Conventional transarterial chemoembolization versus drug-eluting bead transarterial chemoembolization for the treatment of hepatocellular carcinoma is discussing recent clinical approaches  related to this techniques.

Abstract

Background

To compare the overall survival of patients with hepatocellular carcinoma (HCC) who were treated with lipiodol-based conventional transarterial chemoembolization (cTACE) with that of patients treated with drug-eluting bead transarterial chemoembolization (DEB-TACE).

Methods

By an electronic search of our radiology information system, we identified 674 patients that received TACE between November 2002 and July 2013. A total of 520 patients received cTACE, and 154 received DEB-TACE. In total, 424 patients were excluded for the following reasons: tumor type other than HCC (n = 91), liver transplantation after TACE (n = 119), lack of histological grading (n = 58), incomplete laboratory values (n = 15), other reasons (e.g., previous systemic chemotherapy) (n = 114), or were lost to follow-up (n = 27). Therefore, 250 patients were finally included for comparative analysis (n = 174 cTACE; n = 76 DEB-TACE).

Results

There were no significant differences between the two groups regarding sex, overall status (Barcelona Clinic Liver Cancer classification), liver function (Child-Pugh), portal invasion, tumor load, or tumor grading (all p > 0.05). The mean number of treatment sessions was 4 ± 3.1 in the cTACE group versus 2.9 ± 1.8 in the DEB-TACE group (p = 0.01). Median survival was 409 days (95 % CI: 321–488 days) in the cTACE group, compared with 369 days (95 % CI: 310–589 days) in the DEB-TACE group (p = 0.76). In the subgroup of Child A patients, the survival was 602 days (484–792 days) for cTACE versus 627 days (364–788 days) for DEB-TACE (p = 0.39). In Child B/C patients, the survival was considerably lower: 223 days (165–315 days) for cTACE versus 226 days (114–335 days) for DEB-TACE (p = 0.53).

Conclusion

The present study showed no significant difference in overall survival between cTACE and DEB-TACE in patients with HCC. However, the significantly lower number of treatments needed in the DEB-TACE group makes it a more appealing treatment option than cTACE for appropriately selected patients with unresectable HCC.

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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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