History of Ablative Therapies for Barrett’s and Superficial Adenocarcinoma




Abstract


This chapter focuses on historical trends of endoscopic ablation of Barrett’s esophagus (BE) and intramucosal esophageal adenocarcinoma (EA). Background is provided with regard to endoscopic management using ablative therapies in nondysplastic BE as well as BE with low- and high-grade dysplasia/intramucosal EA. In-depth reviews are provided for photodynamic therapy, argon plasma coagulation, laser therapy, multipolar electrocautery, and heat probe therapy including technical endoscopic application, eradication and recurrence rates, and intermodality comparisons.




Keywords

History, ablative therapies, Barrett’s esophagus, PDT, APC, laser, MPEC, heat probe

 





Introduction


A general outline of this chapter includes a brief background followed by historical trends of endoscopic ablation (with the exception of radiofrequency ablation and cryospray ablation, which are covered in chapter 11 , chapter 12 : Radiofrequency Ablation and Cryospray Ablation) for nondysplastic Barrett’s esophagus (BE), BE with low-grade dysplasia (LGD), and BE with high-grade dysplasia (HGD)/intramucosal esophageal adenocarcinoma (EA). Finally, therapeutic options for endoscopic intervention are addressed detailing technical application, eradication and recurrence rates, complications and limitations of treatment, and intermodality comparisons.



Background


For decades, esophagectomy was the only reported treatment for dysplastic BE or EA. This changed in the early 1990s, with the publication of data showing successful ablation of nondysplastic BE using laser therapy . Since then, multiple modalities have evolved intended for the ablation of BE, including multipolar electrocautery (MPEC), argon plasma coagulation (APC), photodynamic therapy (PDT), and more recently cryospray and radiofrequency ablation (RFA) therapies. Unfortunately, for most of these modalities, and especially the older technologies, the current body of literature lacks rigor and primarily consists of case series with “marked heterogeneity around study endpoints, duration of follow-up, postablation surveillance protocols” . Newer interventions, including radiofrequency ablation and cryotherapy, are backed by more rigorous data and are covered in separate chapters (see chapter 11 , chapter 12 : Radiofrequency Ablation and Cryospray Ablation). Furthermore, multimodal endoscopic therapy, or endoscopic resection of visibly abnormal tissue followed by endoscopic ablation of remaining BE tissue, is currently well regarded as a comprehensive and efficacious treatment for BE with HGD or superficial adenocarcinoma . Historically, esophagectomy has been employed as the recommended treatment for EA with drawbacks of high short-term (postprocedural) morbidity, estimated at 6–37% . With advancements in endoscopic therapy for mucosal disease (ie, high-grade dysplastic disease or adenocarcinoma confined to the mucosal layer), new data shows that endoscopic ablation has comparable survival outcomes with less morbidity and is more cost effective than surgery . The current body of research provides critical data and insight into historical practices and guides current clinical decision making and management of BE using ablative techniques, thus we will compare and examine these techniques in this chapter ( Table 10.1 ).



Table 10.1

Summary Table of Ablative Therapies




























































































Category of Therapy Ablative Therapy Eradication Rates Advantages Disadvantages
Photochemical PDT 40–77% Available RCT data Buried glands
Challenging to administer
Long-term data High cost
Risk of photosensitivity reactions
Photothermal Nd:Yag, KTP:Yag laser 28–100% Wide availability Buried glands
Challenging to administer
Limited long-term data
No RCT data
Thermal RFA 82–98% Available RCT data High cost
Less buried glands Limited availability
Low complication rate Limited long-term data
Thermal APC 67–86% Available RCT data Buried glands
Low cost High regression rates
Wide availability Practical for very short segments of BE only
Thermal Cryotherapy 68–88% Low complication rate Limited quality of evidence for use
Low cost Limited long-term data
Thermal MPEC 65–77% Low cost Limited long-term data
Limited quality of evidence for use
Wide availability
Postprocedure dysphagia/odynophagia
Thermal Heater Probe 100% a Low cost Buried glands
Limited long-term data
Limited quality of evidence for use
No RCT data

Abbreviations : PDT, photodynamic therapy; RCT, randomized control trials; RFA, radiofrequency ablation; APC, argon plasma coagulation; Nd, neodymium; Yag, yttrium aluminum garnet; KTP, potassium titanyl phosphate; MPEC, multipolar electrocautery.

a Findings based on one study available in the literature.






Endoscopic Ablation: History and Overview


Endoscopic eradication of high-grade dysplastic BE or superficial EA utilizes ablative therapy to destroy dysplastic cells. The ablated neoplastic mucosa is then replaced with “neosquamous” epithelium, which theoretically decreases the risk of malignancy. This re-epithelialization was first demonstrated in the 1990s in cases of nondysplastic BE using lasers to achieve deep tissue injury. This was particularly efficacious if concomitant high doses of an oral proton pump inhibitor (PPI) were administered . Subsequent trials using PDT, APC, MPEC, RFA, and cryospray therapy followed in the footsteps of the initial laser therapy case series. Laser therapy for ablation of BE was eventually rendered obsolete by the increasing evidence for use of these other therapies. Expansion of endoscopic options for treatment has been met with enthusiasm as historically BE with HGD or superficial adenocarcinoma may have been subjected to morbid surgery .





Endoscopic Ablation as a Treatment Paradigm


The advantage of these mucosal ablation techniques over surgical treatment with esophagectomy is complete eradication of dysplastic or carcinomatous tissue without the operative risk and long recovery periods associated with esophagectomy. Furthermore, it is a potentially curative option for patients who are otherwise considered nonsurgical candidates. There is little long-term data comparing ablative therapy with surgery; however, in two larger retrospective studies, long-term outcomes were comparable between patients receiving endoscopic therapy for mucosal EA and esophagectomy . These authors also note an increasing trend in utilization of endoscopic ablation over time, likely a result of improvement in endoscopic technologies and preferential avoidance of the aforementioned morbidity of esophageal resection .


However, with regard to the merits of endoscopic ablation, it is important to consider the appropriate timing of this intervention within the treatment framework for BE. In contrast to mechanical resection with techniques like endoscopic mucosal resection (EMR), endoscopic submucosal dissection (ESD), or esophagectomy, endoscopic ablation does not produce a specimen posttreatment for pathological evaluation. Because of this, patients with suspected superficial adenocarcinoma should be T-staged with either endoscopic ultrasound (EUS) and/or EMR prior to undergoing ablative therapy. Meta-analysis estimates risk of progression from HGD to EA at 6% per year . As such, society guidelines recommend EUS with EMR of visibly dysplastic or malignant lesions prior to ablation to assess likelihood of disease progression . This recommendation is particularly salient in patients with nodular findings who are at an increased risk of malignancy and lymph node metastases, given the higher probability of submucosal invasion, and therefore not amenable to ablative intervention which has a role only in cases where neoplasia is limited to the mucosa . After EUS is obtained, patients more suitable for endoscopic ablation, in addition to meeting criteria for disease limited to the mucosal layer, include cases of BE with HGD but without esophageal cancer (EC), shallow EC smaller than 2 cm in diameter, favorable histology (moderate or well differentiated), and patient agreeability to endoscopic surveillance program.


An additional drawback for endoscopic ablation includes the posttreatment risk of developing “buried glands” defined as metaplastic glands within the lamina propria with or without dysplasia hidden beneath the neosquamous epithelium. The deep location of the buried metaplastic glands eludes macroscopic detection by conventional endoscopy and therefore presents a risk for progression to neoplastic disease. The true neoplastic potential of this phenomenon is unknown; however, this may explain the metachronous neoplasia noted in long-term follow-up studies of endoscopic ablation.


In the current state of the art, there is data that suggests improved outcomes can be achieved with complete obliteration of all metaplastic tissue even in nondysplastic areas of BE, which prevents the development of neoplastic disease . Additionally, PPI therapy is likely to decrease development of dysplastic changes in BE . As such, mucosal ablation in conjunction with acid suppression therapy using PPI would likely optimize the tissue environment for generation of neosquamous epithelium while simultaneously reducing the risk of recurrent dysplasia. Presently, there exist no established dosing guidelines for administration of PPIs, but a recent position statement of the American Gastroenterological Association recommends standard doses of acid reduction agents to effectively treat GERD and heal esophagitis . Further, empiric PPI use is recommended for neoplastic prophylaxis in documented cases of BE, though the evidence for this indication has not been proven in long-term controlled trials. As a result, it is acknowledged that this treatment model merits discussion of risks and benefits with the patient such that therapy may proceed in an informed manner .



History of Endoscopic Therapy for Patients Without Dysplasia


The bulk of the available research regarding endoscopic therapy for nondysplastic BE examines the application of thermal ablation techniques (ie, laser, MPEC, and APC). Close to complete eradication of nondysplastic BE is likely to have occurred in the majority of these cases; however, the clinical significance of this achievement is unclear. Some studies show that BE without dysplasia still carries a risk of progression to LGD, HGD, and even EA; however, these data also indicate that prophylactic effects of complete ablation of nondysplastic tissues against EC, if any, is unknown . Additionally, the durability of the result to prevent recurrent metaplasia is also in question. Presently, many GI societies (including the ASGE and AGA) do not recommend ablation for nondysplastic BE and instead recommend endoscopic surveillance with biopsies at a 3- to 5-year interval .



History of Endoscopic Therapy for Patients with Low-Grade Dysplasia


There exists very little data on endoscopic therapy outcomes for LGD due to lack of consensus among pathologists and gastroenterologists regarding the natural history of the disease and difficulty making a histopathologic diagnosis. In most of the available literature, patients with LGD are included as a subgroup population for larger studies that focus on nondysplastic BE or HGD. In trials designed to compare the efficacy of PDT and APC, eradication rates were comparable for cases of LGD . More recently, one study demonstrated that use of RFA significantly reduces the risk of progression from LGD to over a 3-year follow-up period compared to endoscopic surveillance alone . Current society guidelines for management of BE with LGD involve either endoscopic surveillance every 6–12 months or endoscopic ablation with RFA .


Despite this, consensus regarding treatment of LGD remains difficult to achieve due to challenges inherent to the diagnosis of LGD. This is likely attributable to poor inter- and intraobserver correlations in the diagnosis of LGD, which even at the histopathologic level is difficult to distinguish from inflammatory changes secondary to chronic reflux disease. Additionally, there exists wide heterogeneity around the known natural history of LGD, which presents difficulties in determining how aggressively surveillance and treatment should be conducted . A meta-analysis conducted by Almond et al. examined LGD diagnoses across 37 studies (6 controlled clinical trials, all other observational) involving 521 patients . Treatments included 9 RFA, 5 PDT, 9 APC, 2 MPEC, 3 laser, and 9 combination (surgical plus ablation) therapies. The authors concluded that LGD is likely over diagnosed and endoscopic ablation is unlikely to reduce risk of neoplastic progression; however, they acknowledged heterogeneity among studies with short-term follow-up which somewhat confounds this data. Due to these challenges, the existing literature concerning the efficacy of endoscopic therapies for the treatment of LGD is limited at best. Barring new information clearly defining the likelihood that BE with LGD leads to malignancy absent medical intervention, the long-term effects of endoscopic ablation remain epistemologically indeterminate.



History of Endoscopic Therapy for Patients with High-Grade Dysplasia or Intramucosal Adenocarcinoma


Initial evidence to support endoscopic treatment of HGD in BE is primarily derived from a meta-analysis of 4 studies and 236 patients, which reported a weighted incidence of EA at 6.58 per 100 patient-years (95% CI 4.99–8.46) during the initial 1.5–7 years after HGD diagnosis . This high rate of progression to malignant disease has since prompted more aggressive treatment of cases of BE with HGD .


Endoscopic therapy is curative for cases where disease is limited to the mucosa , and EMR has been proven to be a durable and effective treatment for remission of neoplastic changes in BE . The combination of EMR followed by endoscopic ablation is particularly effective. In one large, long-term study of 1000 patients, treatment with EMR demonstrated early eradication rates of 96.3% and subsequent development of metachronous neoplasia at a rate of 14.5% was successfully treated with endoscopic retreatment in 115 of 140 patients . Risk factors for cancer recurrence include patients who did not receive post-EMR ablation of remnant areas of BE, patients with poorly differentiated EA, and patients with long segment BE. ESD appears to be a feasible treatment option for patients at risk for incomplete EMR or with poor pathologic procurement with EMR. However, this alternative is limited by the number of available practitioners who perform this therapy and complications like esophageal perforation . Because of this, EMR should be performed on HGD/mucosal EA cases to clarify extent of disease and provide pathologic T staging. High-resolution endoscopic exam should be performed in any biopsy confirmed cases of BE with HGD to detect visible abnormalities amenable for EMR . As mentioned previously, patients with submucosal EA should undergo esophagectomy .





Endoscopic Therapies



Photodynamic Therapy


PDT capitalizes on the interaction between a class of photosensitive drugs and a specific wavelength of laser light that elicits a photoexcitatory reaction. The microvasculature of the targeted tissue is damaged by the photochemical reaction leading to eventual cellular necrosis ( Fig. 10.1 ). The degree of damage incurred is related to the type and concentration of the photosensitizing drug and the wavelength and energy of light delivered endoscopically . The intrinsic macromolecular structure of these drugs preferentially concentrates the drug within skin, reticuloendothelial tissues, and neoplastic growths, making them an effective agent for targeted ablation of tissues. Different formulations of chlorine, chlorophyll, and porfimer contribute to the number of therapeutic options for PDT; however, in the United States, porfimer sodium is the only approved option for systemic use. Globally, 5-aminolevulinic acid (ALA) is also employed, however, it is not approved for systemic use in the United States.




Figure 10.1


Barrett’s esophagus pretreatment (left). Three days posttreatment with PDT (right).

Source: Images courtesy of Michael Kimmey, M.D.



Procedure


Porfimer sodium is the only photosensitive drug currently used for PDT in the United States and activates at wavelengths 515 and 630 nm. The general therapeutic application of PDT in the United States involves reconstitution of porfimer sodium in normal saline or 5% dextrose that is typically dosed at 2 mg/kg administered intravenously over 3–5 minutes. Due to the photosensitive nature of the compound, the slurry must be protected from any light exposure once reconstituted. Light treatment is performed at 40–50 hours after intravenous infusion to allow the majority of drug to be cleared from normal tissues. Typical metabolism of the chemical occurs within 40–72 hours. Porfimer sodium is contraindicated in patients taking other photosensitizers including fluoroquinolones, griseofulvin, phenothiazines, sulfonamides, sulfonylurea, tetracyclines, and thiazide diuretics.


The application of PDT involves deploying a cylindrical centering balloon that stabilizes a diffusion catheter which serves as the light delivery device. The balloon is inflated within the esophageal lumen to stabilize the optical fiber to equilibrate the circumferential distribution and intensity of light. Light dosimetry (joules per centimeter) for BE with HGD is 150–200 and 300 J/cm for EA; this quantity is calculated by multiplying power output of the diffuser (watts) by treatment time (seconds) divided by diffuser length (cm). Currently, the Diomed 630 PDT Laser Model 2TUSA (Diomed Inc., Andover, MA) is the only FDA-approved light source for administering PDT for use with porfimer sodium, which simplifies the calibration process . The endoscopist inputs information regarding the target organ, pathology, and fiber length from which the device automatically calibrates dosimetry (light power and duration). Treatment plans can be altered from standard guidelines to include repeat treatments for missed or “skipped” lesions, or following debridement of adenocarcinoma.


Limitations of treatment using PDT with porfimer sodium include acute toxicities of photosensitizing agents, systemic phototoxicity, and local effects from therapy. The most common postprocedural complaints include odynophagia and chest pain, abdominal pain, nausea and vomiting, fever, and pleural effusion. Rare adverse effects include anemia related to bleeding from mucosal ulceration, esophageal perforation, atrial fibrillation, and respiratory compromise. Local complications of scarring including esophageal stricture formation reported at upwards of 58% of cases typically occurring about 1–2 months after treatment ( Fig. 10.2 ). Frequency of side effects is correlated with higher light dosage and amount of therapeutic exposure (ie, type of pretreatment, time between treatment sessions, and number of treatment sessions) .




Figure 10.2


Healed esophagus 3 months post-PDT (left). Esophageal stricture post-PDT (right).

Source: Images courtesy of Michael Kimmey, M.D.


PDT is contraindicated in patients with esophageal or gastric varices, esophageal ulcers >1 cm, esophageal fistulae, porphyria or sensitivity to porphyrins, or esophageal tumors with vascular invasion. Patients must be compliant with photosensitivity precautions including full skin coverage with hat, eyewear, complete clothing of limbs, etc. for at least 30 days postdrug administration to minimize risk of cutaneous phototoxicity.



PDT Compounds


Outside of the United States, PDT photosensitization using ALA is common. ALA is a metabolic precursor of the compound protoporphyrin IX and can be administered orally. 5-ALA PDT has demonstrated greater efficacy over porfimer sodium PDT for BE segments <6 cm . These findings have been attributed to a number of factors including a higher mucosal (vs submucosal) concentration of the drug. An additional benefit of ALA over porfimer sodium is a shorter half-life of the 5-ALA compound which results in an increased rate of tissue clearance thereby decreasing the probability of adverse photosensitivity reactions and less esophageal stricturing . Transaminase abnormality is associated in 50% of cases using ALA but is typically transient, lasting 3–4 days.



Efficacy


PDT using porfimer sodium was the first endoscopic ablation technique proven to reduce malignancy risk using randomized clinical data and has been used since the 1970s to treat other cancers . However, contemporary utilization of PDT has diminished in favor of RFA after a clinical trial comparing PDT to RFA showed superior therapeutic efficacy, cost, and reduced complication rates in the RFA group . PDT eradication rates are documented in the literature in the range of 77–100% based on observational studies . One randomized placebo controlled trial demonstrated significantly higher rates of eradication using PDT with PPI (77%) versus PPI alone (39%) ( p <0.0001) . Five-year follow-up data from the same group demonstrated significant difference in durability as evidenced by regression rates in the PDT-treated groups (15%) versus PPI treated alone (29%) .


Other studies demonstrate durable response to PDT but note a greater risk of buried metaplasia with PDT when compared with RFA and documented occurrences of subsquamous adenocarcinoma .


Nonrandomized control trials (RCT) of PDT using 5-ALA demonstrated efficacious treatment of HGD and early EA . The first randomized trial of PDT using 5-ALA demonstrated significant macroscopic regression over placebo photosensitizer in treatment of BE with LGD .

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Feb 12, 2019 | Posted by in GASTROENTEROLOGY | Comments Off on History of Ablative Therapies for Barrett’s and Superficial Adenocarcinoma
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