Robert

K. Zeman,

MD

#{149} Firas

Al-Kawas,

MD

Gallstone Lithotripsy: for Optimism?3 Many institutions are entering the final phase of their data collection in the investigation of the safety and clinical efficacy of gallstone bithotripsy. Although until recently there have been virtually no published reports of the U.S. gallstone bithotripsy experience, the pros and cons of this treatment have been extensively debated in the medical literature and lay press. From its inception, the hype surrounding the field created an atmosphere of unrealistic expectations. As hard data become available, it is increasingly important that we become able to distinguish those issues that have been resolved from those that have not. Lithotripsy is not a miracle or overnight cure for cholelithiasis. It will not be a source of windfall profits for institutions or physicians. We are optimistic that lithotripsy will retain a role in the treatment of cholelithiasis. This cause for optimism is our improved understanding of treatment factors and patient selection criteria that influence outcome. We have also learned some valuable lessons regarding the dissemination of new technology. In the final analysis, lithotripsy works well in selected patients while resulting in minimal side effects.

THE SCIENCE OF FRAGMENTATION AND FRAGMENT CLEARANCE For a patient to become free of stones requires fragmentation followed by fragment evacuation. Because both of these processes are complex, results have varied greatly among centers performing biliary lithotripsy. Although fragmentation may be partially predicted on the basis of the laws of physics, fragment evacuation is far more mysterious.

Attempts

clearance have met

to rebate

fragment

to gallbladder contractility with only limited success

(1).

3

From

sion

Departments Medicine,

(F.A.K.,

Medical

DC accepted

quests

Volume

Georgetown

3800

20007.

of Radiology Gastroenterology

S.B.B.),

Center,

ington, 1990;

the and

Reservoir

Received

October

Rd

#{149} Number

NW,

September 20.

Address

to R.K.Z.

178

DiviUniversity

1

Wash28,

reprint

re-

B. Benjamin,

Is There

MD

Still

Cause

Most investigators believe ursodiob therapy plays a role adjunctive to that of lithotripsy. At the same time, many of our patients have not shown the 1mm-per-month dissolution of stones and fragments that the literature had led us to anticipate (2,3). Regardless of the factors that cause fragment dissolution or evacuation, fine pulverization of stones during bithotripsy is the single most important factor in making patients free of stones. Our experience tells us that patients whose fragments were pulverized to no larger than 2-3 mm during lithotripsy are more likely to become stone free than those with 56-mm fragments. Other investigators have also suggested that patients with the smallest fragments after lithotripsy become free of stones the fastest (4). If the key to becoming stone free is effective fragmentation of gallstones, what elements influence fragmentation? Fragmentation occurs because of the pulsed compressive and rarefactive forces associated with shock waves. Compressive force of 1,000 bar (atmospheres) or higher can be generated with commercially available lithotriptors (5). Each shock wave also harbors a rarefactive or negative pressure component as low as 50 bar (6). Although the influence of peak pressures on fragmentation continues to be debated,

tors select an appropriate fragment size as the end point of lithotripsy? There is no question that heavy stone burden adversely affects fragmentation and fragment evacuation. Limiting the stone burden through a criterion that combines stone number and size makes sense for patient selection. Solitary stones respond the best, and most of our patients that are stone free within 6 months of treatment had solitary stones. Stone architecture may also affect fragmentation. Initial work had suggested no relationship between stone composition and the efficacy of fragmentation. Many protocols in the United States allow treatment of radiopaque or minimally calcified stones as determined on a plain abdominal radiograph. Findings from recent work at our laboratory, however, suggests that stones rich in cholesterol exhibit more rapid and homogeneous fragmentation than do stones containing a focal rim or internal pigment (7). Cholesterol crystals follow a more orderly, radial distribution than pigment deposits. This tends to promote the development of clefts and fissures deep within the stones as fragmentation occurs. In light of the inverse relation between stone density and cholesterol content, it is not surprising that Rawat and Burhenne found that calcified stones re-

there

quire

is agreement

that

the

cumulative

number of shock waves delivered closely predicts the extent of pulverization. Fragment size diminishes exponentially with increasing numbers of shock waves (7). In attempting to duplicate the results of researchers at the Kbinikum Grosshadern in Munich, investigators in the United States have publicly expressed frustration at limitations in power, number of shock waves, or number of treatments permitted under Investigational Device Exemption protocols in the United States. These limitations were included in some

margin

(R.K.Z.)

Stanley

protocols

despite

the

increased

of safety and reduced tissue injury associated with second-generation, large-aperture, tightly focused shock wave generators. The flexibility to aggressively reduce the size of stone fragments is essential in producing a stonefree patient and lessening the risk of fragment impaction. We must interpret outcome data cautiously and keep in mind the question, did the investiga-

greater

energy

and

increased

number of shock waves to achieve fine pulverization (8). The recent work of Brakeb et a!, using computed tomography (CT) to predict stone cholesterol content clinically (9), confirms earlier in vitro work (10) and suggests a possible role for CT in the selection of stones that are rich in cholesterol and easiest to fragment. The rarefactive component of shock waves produces cavitation effects that manifest as microbubble formation in the path of the shock wave. These microbubbles appear as echogenic “flashes” and, when in the gallbladder, can sonographically mimic stone fragments during lithotripsy (11). There is general agreement that microbubbles agitate and erode fragments and play an important role in producing fine particles (12). Since fluid supports cavitation effects better than does solid tissue, positioning the patient such that stones

are

is therefore

surrounded

desirable

by

abundant

to achieve Radiology

bile

great#{149} 33

est fragmentation (13,14). Contracting the gallbladder helps limit stone movement and makes targeting easier, but it could compromise fragmentation through reduction in cavitation. This trade-off has yet to be fully evaluated clinically. Regardless of the best strategy, sonographicably evident microbubbles that form in bile adjacent to a targeted gallstone are usually a harbinger of good results and something we book for during actual treatments (13,14). Targeting is one element of the fragmentation process that has not received sufficient attention (15). Stones and barge fragments must be kept in the high-power focal zone of the shock wave. A blast path must be selected that limits respiratory movement of the gallbladder, avoids the duodenum and kidney, and “pins” stones against an area of the gallbladder where they will not excessively deflect away from the incoming shock waves (15). The blast path must be as short as possible, since shock waves are attenuated and defocused as they go through tissue (16). Even with 10 years of ultrasound (US) experience, we still find these targeting challenges formidable. Having trained radiologists and nonradiologists (gulp, Dr Zeman admits it!), we can honestly say that the ability to break stones is most closely predicted on the basis of the US training and knowledge of cross-sectionab anatomy of the treating physician. Frequent retargeting is essential (17). Investigators at the Klinikum Grosshadern, despite being nonradiobogists, had extensive background in US. Virtually none of the vendors conducting lithotripsy tnals required documented US training of their investigators in the United States. As one sales representative put it, “That’s a professional issue, doctor. We’ve placed our machines based on market data reflecting the ultimate buyers of machines, not the users’ expertise.” While that position can be rationalized by some, it should not be surprising that results will vary greatly among sites.

WHAT ABOUT

HAVE WE LEARNED DISSEMINATION OF TECHNOLOGY?

At one point or another most academicians are asked to participate in a clinical trial of a new technology or new drug. It is easy to be swept up in the enthusiasm for a new treatment as vendors rush to be first out of the gate in a new market and as subspecialties scramble to corner a new discipline. As physicians, we must always insist that good study design and scientific logic do not take a back seat in the regulatory process. In the area of gallstone 34

#{149} Radiology

lithotripsy, many external forces are at work. The investigators, the vendors, and the FDA all deserve a share of the blame for the shortcomings in protocol design and data collection. Mixed signals from the FDA had bed most vendors to believe that lithotnipsy could be compared against “historical” controbs for treating gallstones. This means that the outcome of bithotnipsy with adjunctive ursodiob therapy could be compared against preexisting data on the response rate of gallstones to ursodiol alone. These data largely existed in the gastroenterology literature and in Ciba-Geigy’s (Summit, NJ) new drug application for the drug Actigall (ursodiol). After most studies were nearing completion, the FDA “suggested” adding a new “ursodiol-only” limb to the treatment protocol. Prospectiveby determining whether lithotnipsy plus ursodiol therapy outperforms ursodiol therapy alone is not unreasonable. Unfortunately this change in direction substantially alters many protocols aften the fact. it will influence patient recruitment and introduce delays in the regulatory process that could have been avoided. The bad experience of some vendors who pushed for early biliary lithotnipsy hearings by the Gastroenterology Urology Device Section Advisory Panel of the FDA has given much of the field a black eye. To hope that mediocre stone-free rates at 6 months were sufficient for approval was not realistic. Even in the face of excellent fragmentation, fragment clearance is slow and may not be adequately reflected at 6 months. The negative press surrounding the FDA hearings has reduced patient recruitment. The high cost of the procedure in many institutions has also wiped out patient interest, as this procedure is often not reimbursed by third-party payons. In centers where patients are being asked to bear significant out-of-pocket expenses, treatment has dramatically declined. Laparoscopic cholecystectomy has quickly been embraced as the new standard of care in treating gallstones. The rapidity with which the procedure has become accepted is due to many factors. It is widely available, not dependent on expensive equipment in a big medical center, and more user-dniven than lithotnipsy. Despite being unproved, the procedure can be marketed without the restrictions and investigational disclaimers required for lithotripsy. Many insurers are reimbursing for laparoscopic cholecystectomy at the same or even higher rate than conventionab cholecystectomy, all this with no large refereed series confirming the safety (vis-#{226}-vis bile duct injuries) or efficacy of this treatment. If patients must choose between a procedure that

their scopic

insurance will pay for (laparocholecystectomy) versus one they will have to pay for themselves (bithotnipsy), the choice is clear.

PROSPECT

FOR

THE

FUTURE

Maglinte et al, in quoting their expenience, have eloquently delineated the arguments against lithotnipsy. Acute cholecystitis requiring emergent cholecystectomy is an exceedingly rare sequela of bithotnipsy. In our treated population, which is similar in size to that of Maglinte et al, only one middle-aged patient had acute inflammation found at the time of cholecystectomy following 72 hours of intermittent colic. This patient had 6- and 8-mm fragments and was awaiting additional treatment. Our dedication to producing small fragments has led to only four patients haying continued attacks of colic beyond the first postlithotnipsy week. As in Indianapolis, about half of our patients have biliary colic within the first few days of lithotripsy. The vast majority of patients who undergo lithotripsy feel better after the procedure than they did before it. This may be due to the effects of the adjunctive ursodiol we administer, but regardless, it appears that the quality of life is objectively improved after therapy (18). The risk of stone recurrence after successful lithotripsy and stone dissolution is real. We cannot yet say how many patients will have recurrence. It has been popular to guess that about half of patients will have a recurrence within 5 years, based on data from the National Cooperative Gallstone Study. In that study, patients were treated with chenodiol therapy (a relative of ursodiob), and therapy was discontinued after patients were deemed stone free on the basis of oral cholecystographic (OCG) findings. Overall recurrence plateaued at 40% (19). Since only OCG was used to determine which patients initially became stone free, some patients may have had small residual calculi that were missed at OCG. As these stones grew and became larger than 5 mm, they were detected and incorrectly labeled recurrence. A smaller, more recent study using US and OCG to evaluate the gallbladder after chenodiob therapy demonstrated a recurrence rate of only 26% with a median followup of 30 months (20). Life-table analysis of the first 58 patients to become stone free following lithotnipsy and adjunctive bile salt therapy at the Klinikum Grosshadern has revealed a relatively low rate of recurrence (11% to 3 years) (21). This may be due in part to patient selection, as the patients treated had predominantly solitaly stones and a light stone burden. Ultimately, we will know whether the

January

1991

patient selection criteria for lithotnipsy, compared with the more liberal criteria used for PCCL or MTBE therapy, reduce the likelihood of recurrence. We will also learn the relative responsiveness of recurrent stones to repeat lithotripsy or dissolution. In the meantime, there is no escaping the risk of recurrence following gallbladder-preserving treatments for cholelithiasis. Over time we will learn the magnitude of this problem. The incidence of carcinoma of the gallbladder is low but may rise slightly if the number of cholecystectomies dedines (22). Despite the known relationship between carcinoma and cholelithiasis, we do not know the effect on cancer risk of rendering patients stone free. The absence of stones and presumably reduced symptomatic attacks may reduce chronic inflammation and carcinogenic potential. Any conclusions about carcinoma risk are sheer speculation at this point. Elective cholecystectomy has a very low mortality regardless whether it is performed by means of the conventional or laparoscopic route. Yet to say that it is universally “definitive” is misleading. The most recently published cholecystectomy series showed that 12% of patients undergoing elective gallbladder removal for symptomatic stones had residual or recurrent symptoms (23). This was despite the fact that 90% of patients underwent intraoperative chobangiography to exclude retained duct stones in this series. In centers where cholangiography or choledochoscopy may not be as readily available, the incidence of postchobecystectomy syndrome may even be higher. To our knowledge, no studies have compared procedure-related morbidity in comparable populations undergoing lithotripsy versus cholecystectomy. Cholecystectomy

is here

to stay.

The

appeal of the laparoscopic approach will substantially reduce the pool of patients for lithotnipsy. Lithotnipsy devices capable of treating gallstones will not be ubiquitously available. In specialized centers where kidney and common duct stone lithotripsy are also performed, the equipment cost can be justified. Once additional complication and long-term follow-up data for both

laparoscopic cholecystectomy and lithotripsy become available, the playing field wibl be more even. Lithotripsy will continue to be a viable treatment option for patients with a light stone burden (especially single stones) without calcification. It is an outpatient procedure and does not require any mcisions or general anesthesia. It entails little risk as long as fragmentation is adequate to produce small fragments. Because of adhesions, patients who have had prior bouts of acute cholecystitis or who have undergone upper abdominal surgery are not candidates for laparoscopic cholecystectomy at many centers but may be candidates for lithotnipsy. Even if 5,000, not 500,000, patients undergo lithotripsy each year, refinements in our ability to use this technology and new applications will continue to thrive in centers of excellence dedicated to this science. U

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#{149} 35