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Annals of Surgery Journal Club
Interactive resource for surgery residents and surgeons to discuss and critically evaluate articles published in Annals of Surgery selected by a monthly guest expert who will review an article each month, offer questions and respond to reader's comments.
Wednesday, July 02, 2014
Moderator: Jean-Nicolas Vauthey, MD
 

Featured Article: Phase II Trial of Hepatic Artery Infusional and Systemic Chemotherapy for Patients With Unresectable Hepatic Metastases From Colorectal Cancer: Conversion to Resection and Long-term Outcomes. D’angelica MI, Correa-Gallego C, Paty PB, et al. Ann Surg. 2014 Mar 21. [Epub ahead of print]

 

Summary:

The rate of conversion of unresectable colorectal liver metastases (CRLM) to resectable CRLM has improved with modern systemic chemotherapy and biologic therapy. Results of recent studies, including randomized trials, report conversion rates of 20-38%. The combination of hepatic artery infusional (HAI) chemotherapy with systemic chemotherapy has become an attractive option for the treatment of unresectable CRLM owing to the high response rates observed in previous published studies.

This prospective phase II trial aimed to evaluate, as a primary endpoint, the conversion rate to complete resection (resectability rate) in patients with unresectable CRLM treated with HAI fluorodeoxyuridine (FUDR) in combination with systemic chemotherapy including bevacizumab.

Technical and biological criteria were used to define unresectability. Technically unresectable CRLM were those that required resection of 3 hepatic veins, both portal veins, or the retrohepatic vena cava to achieve a negative margin, or those requiring a resection that would leave fewer than 2 adequately perfused and drained segments. Biologically unresectable CRLM were those that included >6 metastases in one lobe, including 1 metastasis ≥5 cm, or those with ≥6 bilobar metastases.

Forty-nine patients with liver-only disease were treated with HAI FUDR in combination with irinotecan and fluorouracil or irinotecan and oxaliplatin with bevacizumab. Sixty-five percent had previously received systemic therapy. The rate of overall grade 3 or 4 toxicity was 41%. After the first 24 patients were enrolled, bevacizumab was removed from the treatment owing to high biliary toxicity (13%; 3 patients required biliary stent placement), and the authors do not recommend the use of the combination of HAI FUDR and bevacizumab. The overall response rate, according to World Health Organization criteria, was 76%; the response rate was 82% in chemotherapy-naïve patients and 72% in previously treated patients. Such response rates led to a resectability rate of 47% (23 patients) at a median period of 6 months from treatment initiation. Resections included a combination of anatomic (17 patients) and non-anatomic multiple resections (6 patients). Radiofrequency ablation was used in 16 patients, and 5 of the 23 patients (22%) had positive margins. Fifteen of the 23 specimens showed a significant pathologic response to chemotherapy (more than 75%), including 3 complete pathologic responses. The median overall survival duration for all patients was 38 months and the median progression-free survival duration was 13 months. As expected, resectability rate was the only factor associated with prolonged overall survival in a multivariate analysis. The 3-year overall survival rate in patients undergoing resection was 80% (compared with 26% in patients who did not undergo resection). After a median follow-up period of 38 months, 20% of patients were disease-free.

The authors conclude that HAI chemotherapy has a potential role in the treatment of unresectable CRLM. How this approach compares with aggressive combination chemotherapy and biologic therapy remains to be studied.

 

References:

Ychou M, Rivoire M, Thezenas S, Quenet F, Delpero JR, Rebischung C, Letoublon C, Guimbaud R, Francois E, Ducreux M, Desseigne F, Fabre JM, Assenat E. A randomized phase II trial of three intensified chemotherapy regimens in first-line treatment of colorectal cancer patients with initially unresectable or not optimally resectable liver metastases: the METHEP trial. Ann Surg Oncol. 2013;20(13):4289-97.

 

Goéré D, Deshaies I, de Baere T, Boige V, Malka D, Dumont F, Dromain C, Ducreux M, Elias D.

Prolonged survival of initially unresectable hepatic colorectal cancer patients treated with hepatic arterial infusion of oxaliplatin followed by radical surgery of metastases. Ann Surg. 2010;251(4):686-91.

 

Hemming AW, Mekeel KL, Zendejas I, Kim RD, Sicklick JK, Reed AI. Resection of the liver and inferior vena cava for hepatic malignancy. J Am Coll Surg. 2013;217(1):115-24.

 

Brouquet A, Abdalla EK, Kopetz S, Garrett CR, Overman MJ, Eng C, Andreou A, Loyer EM, Madoff DC, Curley SA, Vauthey JN. High survival rate after two-stage resection of advanced colorectal liver metastases: response-based selection and complete resection define outcome. J Clin Oncol. 2011;29(8):1083-90.

 

Questions:

1) Usually the future liver remnant is the main factor considered in the definition of unresectability, but in this study, the authors define unresectability as involvement of all 3 hepatic veins or the inferior vena cava. This definition is different from the definition of unresectability used by the Americas Hepato-Pancreato-Biliary Association. That definition specifies complete R0 resection of intrahepatic and extrahepatic disease with preservation of at least 2 adjacent liver segments with adequate vascular inflow and outflow, as well as biliary drainage and an adequate volume of liver (i.e., the future liver remnant) after resection (which usually means at least 20% of the total estimated volume of the liver for normal parenchyma, or 30-60% if the liver is injured by chemotherapy, steatosis, or hepatitis). Should the definition of resectability be limited to anatomical considerations such as those including vascular involvement, as reported by the authors, or should it include functional considerations?

 

2) The inferior vena cava is rarely invaded in colorectal liver metastases and usually is not a site of local recurrence. Moreover, definite vascular involvement or attachment of the hepatic veins is rarely reversed by conversion therapy. What is your opinion about alternative technical approaches for unresectable disease (e.g., 2-stage resection with portal vein embolization, vascular reconstruction of the inferior vena cava or hepatic veins, radiofrequency ablation)? The authors also define biological unresectability as >6 metastases in a single lobe with 1 metastasis ≥5 cm or ≥6 bilobar metastases. Do you use number, size, or bilobar versus unilobar as appropriate criteria to define biological unresectability? Should response to therapy be used as a biological criterion for resectability? Should mutational status of the tumor (RAS) be considered?

 

3) Sixty-five percent of patients received the treatment as second-line therapy after first-line therapy failed. Recent studies indicate adequate safety ratings and a resectability rate of up to 67% with aggressive combined systemic chemotherapy (METHEP trial) in well-defined unresectable CRLM. With the data from recent trials, would you consider more aggressive systemic chemotherapy with the combination of oxaliplatin and irinotecan with or without biologic therapy as an initial approach for all patient s rather than the implantation of a pump?

 

4) HAI chemotherapy with a pump requires a surgical procedure associated with technical complications (a 14% complication rate was reported in the current study), FUDR is not widely available as a pharmacologic agent, and refill and maintenance of the pump requires special expertise. Other centers have reported success with arterial infusion therapy with oxaliplatin, including high resectability rates. Should arterial infusion therapy with oxaliplatin be preferred to HAI FUDR with a pump?

 

 

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.


Monday, June 16, 2014
Moderator: Carlos Fernández-del Castillo, MD
 
Featured Article: A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage"

 Annals of Surgery volume 259, pages 605-612 , April 2014.

Summary:

This is a randomized trial comparing outcomes of patients undergoing pancreatoduodenectomy(PD) with and without intraperitoneal drain placement. Surgeons from 9 academic hospitals (all considered “high-volume pancreatic centers” because they perform around 50 PD/year) agreed to offer participation into the trial to all their patients undergoing PD or distal pancreatectomy. 282 patients were randomized over a 15-month period, of which 226 were resected. 137 of these underwent PD and are the cohort described in the study.  68 patients were randomized to the “drain arm”, and had one or two closed-suction drains left intraperitoneally at the conclusion of surgery (the number, size and brand were at the discretion of the surgeon), and 69 patients had no drains left. In the group with drains, they were removed once the output was 20 ml/day for 2 consecutive days and/or the amylase concentration was < 3 x the upper limit of normal serum amylase, which turned out to be sometime between postop day 5 and 13 (median of 7). All complications within 60 days were recorded, and patients were followed up to postop day 90 to assess mortality. The study originally intended to enroll 752 patients in order to detect a 10% difference  (that would be statistically significant) in the rate of grade II or more complications between groups.  However, the study was stopped early by the Data Safety Monitoring Board because of excess mortality in the patients undergoing PD without drains.

As expected in a study with good randomization, the two groups were comparable regarding gender, age (mean 63 y), comorbidities, BMI, pathology  (50% had ductal adenocarcinoma), laparoscopic approach (8%), need for vascular resection (18%), and type of pancreatic anastomosis (the most frequent was an end-to-side, duct-to-mucosa).  Operative time (416 min) and need for blood transfusion (7%) were also similar in both groups. 

 The overall number of complications and the complication severity were significantly higher in patients undergoing PD without drainage. Specifically, delayed gastric emptying  (42% vs 24%), intra-abdominal abscess (25% vs 12%), other intra-abdominal fluid collections (12% vs 2%) and severe diarrhea (17% vs 2%) were significantly higher in the no drain group. 

Although the 90-day mortality was 4 times higher in the no-drain group (12% vs 3%), this was not statistically significant (P = 0.097).  The lack of significance was also true with the reoperation rate, which was 9% in the no-drain group and 3% in the drain arm (P = 0.274).

 The authors concluded that elimination of intraperitoneal drains  after PD increases severity and frequency of complications, and may directly increase mortality, and therefore cautioned against their abandonment.

Questions:

1)    The “magical” P number for statistical significance is <0.05, yet, the Data Safety Monitoring Board made the decision to stop the trial even though the difference in mortality had a P value of only 0.097.  Why do you think they did do?  It is a lot of work to organize a multi-institutional surgical trial, and one could argue it would have been better to continue the trial until a significant difference in mortality and/or reoperation were found.  Can you define what a P value of <0.05 means?  Are all statistically significant differences “clinically” significant and vice versa?  What is a Data Safety Monitoring Board?  Do all clinical trials have to have one?  The mortality in the drain-group was 3%, and in the no-drain 12%. Assume that the mortality in the no-drain group (which is an acceptable mortality for PD) remained the same, how many consecutive patients without mortality would have to be enrolled in the no-drain arm to level off the mortality?

2)   Discuss what is unique in pancreatic surgery, and in particular after PD, that most surgeons around the world continue to leave intraperitoneal drains, whereas routine drainage has been abandoned in practically all other intra-abdominal operations.  To what were the majority of deaths attributed?  One patient in the no-drain group had a laparoscopic PD, was discharged on POD 10, and returned on POD 24 in shock.  He was found to have hemorrhage from the hepatic artery and died.  Can you give potential explanations for this event?

3)   A previous single-institution randomized trial comparing drains vs no drains in PD had in fact shown worse outcomes when drains were used.  Some surgeons in that institution (about half, according to a recent paper published by them)  and others in different parts of the world don’t use drains after a PD.  Do you think it is likely they will change their practice? Those surgeons seem to have good outcomes without using drains; can you come up with potential reasons to explain why the no-drain group in the current study did not do as well?  Is there anything you would have done differently if you were designing this trial?  Name strengths and pitfalls of a multi-institutional vs a single institution trial.

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.

 

 

Wednesday, May 14, 2014
Moderator: Dr. Henry Pitt
 
Featured Articles:

1. Gutt CN, Encke J, Koninger J, et al. Acute cholecystitis: early versus delayed  cholecystectomy:  a multicenter randomized trial.  Ann Surg 2013; 258: 385-393.

2. DeMestral C, Rotstein OD, Laupacis A, et al. Comparative operative outcomes of early and delayed cholecystectomy for acute cholecytitis: a population-based propensity score analysis.  Ann Surg 2014; 259; 1-x.

Summary:

Debate regarding the pros and cons of early versus late cholecystectomy in patients with acute cholecystitis has raged for decades. In the open cholecystectomy era prospective randomized controlled trials (RCT’s) favored early surgery, primarily due to shorter overall length of stay and reduced likelihood of ongoing biliary disease.  Over the past 25 years following the introduction of laparoscopic cholecystectomy, RCT’s again have confirmed essentially the same conclusions.  In the 21st century meta-analyses, population studies, and cost-utility analyses also have favored early surgery.  However, despite the significant weight of these data, considerable variation in practice patterns exist within most countries as well as around the world.                                                                                                                                                                   In the September, 2013 issue of Annals of Surgery Gutt et al1 reported the largest RCT of early versus delayed cholecystectomy for acute cholecystitis.  This multicenter trial from Germany, which was presented at the American Surgical Association, documented that the 75-day morbidity was reduced by three-fold with early surgery (p<0.001). In addition, overall length of stay (LOS) was shortened by 4.6 days (p<0.001) and cost was diminished by one-third.  In the January 2014 issue of Annals of Surgery de Mestra et al2  have added  substantially to the literature by reporting a population-based propensity score analysis of more than 22,000 patients undergoing cholecystectomy for acute cholecystitis in Ontario, Canada from 2004-11.  This report is unique because the authors demonstrated, for the first time, that the risk of major bile duct injury (BDI) and early death are substantially reduced with early surgery.  They also confirmed earlier studies documenting reduced LOS with surgery performed early after presentation.  Taken together these two seminal reports document that patient value (quality/cost) is clearly superior with early surgery for acute cholecystitis.

Questions:

1. Do these seminal papers apply to patients with severe cholecystitis who present with septic shock and/or organ failure?

2. Should frail, very elderly patients with acute cholecystitis undergo early surgery?

3. Despite overwhelming evidence in the literature, why are many patients with acute cholecystitis not managed with early surgery?

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.

 


Thursday, April 03, 2014
Moderator: Dr. Mary Hawn
 
 

 

The study population for this current study is a subset of 264 (69%) of the 366 patients in the watchful waiting group from the original study that agreed to participate in a registry.  The main finding is that while watchful waiting remains a safe strategy with a very low rate of subsequent presentation for an incarcerated hernia, most hernias became increasingly symptomatic ultimately leading to elective repair.  Nearly 70% of patients in the watchful waiting arm crossed over to repair during the 10 year follow-up period.  In Cox proportional hazards analysis, age greater than 65 was the single factor identified with cross over.  The cross over rate for men greater than 65 was 79% versus 62% for men younger than 65.  Thus while watchful waiting is safe, most men, especially older men will ultimately elect to undergo repair of their inguinal hernia.   

 

The findings in this study are useful for shared decision making with men about whether and when to get their inguinal hernia fixed. 

 

While the authors do not specifiy why they chose to dichotomize the age variable at 65 years, it cannot be overlooked that two major policies go into effect in the United States at this age:  eligibility for (1) retirement with social security benefits and (2) Medicare healthcare benefits.

 

Questions: 

1.  Based on the observation of the association between age >65 and crossover to surgery, do you think that age is the determinant of whether men will chose to have their hernia repair, or perhaps is the time available for recovery an important variable? 

 

2.  When discussing management strategies with patients, should we focus on their employment status, disability coverage and activity level in determining the optimal time for elective hernia repair?

 

3.  This study did not report on outcomes of surgery for those men that underwent delayed hernia repair compared with their counterparts that underwent immediate hernia repair.  What could the effects of delayed hernia repair have on ultimate hernia outcomes?

 

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.


Friday, March 07, 2014
Moderator: Dr. Mark Malangoni
 
Featured Article: General Surgery Residency Inadequately Prepares Trainees for Fellowship: Results of a Survey of Fellowship Program Directors by SG Mattar etal. Ann Surg 258:440 - 449, 2013.
 
Summary:

Mattar and coauthors have surveyed a select group of fellowship program directors (FPDs) regarding their opinions about the capabilities of those entering advanced training following completion of a general surgery residency.  Using a Likert scale to assess multiple domains, they report mixed results.  Their opinions of fellows in the domains of professionalism and clinical evaluation were very good with less than 5% of FPDs expressing significant concerns in these areas.  In contrast, more than 25% of FPDs felt that incoming fellows required more supervision than expected, including 18% who believed their fellow could not perform a laparoscopic cholecystectomy - the most common operation done in surgery residency - without supervision.  Concerns about basic and advanced minimally invasive skills were also prevalent and there was great concern about fellows’ interest and abilities in academic and scholarly pursuits.

These concerns are neither novel nor recent; however, this article emphasizes the ongoing unease about the preparedness of surgery residents to pursue further training (the focus of this report) or enter practice.  Proponents pile on with anecdotes reinforcing these findings while others blame duty hours requirements and the need to return to “the good old days,” alleging that these issues didn’t exist in decades past.  While time clouds all memories, most surgeons recognize that the majority of residency graduates, present or past, need some guidance and mentoring in the early years of practice.  If there was nothing further to learn during fellowship, why would these advanced training programs exist?  More importantly, Mattar et al ask an important question: can we do better in training surgery residents for their eventual careers, whether as specialist or sub-specialist surgeons?

This article presents the opinions of one group, the FPDs.  The results and conclusions should give us pause to reexamine the current training paradigm for surgery and use the collective will to provide the best possible training.

Questions:

1.      Do you believe that graduated residents should be capable of unsupervised practice either when entering additional training or going into clinical practice?  Is ongoing mentoring a necessity that should be acknowledged and supported?

2.      Do you agree with the opinions of the fellowship program directors that a large percentage of residents lack appropriate minimally invasive skills at the completion of training?  If you agree, what needs to change to remedy this problem?

3.      Does the presence of a minimally invasive surgery fellowship program interfere with the training of surgery residents?

4.      Would rotations where residents perform a large volume of operations (e.g., in community hospitals) improve training? 

Please feel free to comment on any or all of the questions above. We look forward to hearing from you, the Annals readers. This article can be accessed for free.

   
 
About the Author

Jean-Nicolas Vauthey, MD, FACS
Dr. Vauthey is Chief of the Hepato-Pancreato-Biliary section and Bessie McGoldrick Professor in Clinical Cancer Research in the Department of Surgical Oncology at The University of Texas MD Anderson Cancer Center. Dr. Vauthey’s clinical research has focused on methods to measure and to improve outcome after hepatic resection for hepatobiliary malignancies. Dr. Vauthey has co-authored more than 350 publications in peer-reviewed journals (h-index, 74) and more than 85 reviews and book chapters in major textbooks. He is editor or co-editor of major textbooks devoted to hepatobiliary and pancreatic cancers.

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